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Surrogate markers of HIV infection are, by definition, measurable traits that correlate with development of clinical. AIDS. Although several candidate markers ...
CLINICAL MICROBIOLOGY REVIEWS, Jan. 1994, p. 14-28

Vol. 7, No. 1

0893-8512/94/$04.0O+O

Copyright X 1994, American Society for Microbiology

Markers Predicting Progression of Human Immunodeficiency Virus-Related Disease C. M. TSOUKAS* AND N. F. BERNARD McGill University AIDS Centre, McGill University, Montreal, Quebec, Canada H3G 1A4

INTRODUCTION

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PATHOPHYSIOLOGY SEROLOGIC T-CELL ACTIVATION MARKERS ............................................ ......................

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15 15 16 Neopterin ............................................ sIL-2R............................................ 16 sCD8 ............................................ 17 SEROLOGIC B-CELL ACTIVATION MARKERS ............................................ 17 IgG, IgM, and IgA ............................................ 17 CICs ............................................ 17 ANTIBODIES TO HIV ............................................ 17 17 Anti-p24 ............................................ 18 Anti-gpl20 ............................................ ............................ 2-M ....................

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Anti-p17 ............................................. Anti-gp4l ............................................. Anti-NEF ............................................ OTHER ANTIBODIES ............................................ Lupus Anticoagulant and Anticardiolipin ............................................ Antileukocyte Antibodies ............................................ Anti-sCD4 ............................................ OTHER SEROLOGIC MARKERS .............................................

18 18 18 18 18 18 18 19

TNF.1 .......................................................l9

Acid-Labile Human Leukocyte IFN and 2-5A Synthetase ............................................ ANTIGEN MARKERS .............................................

p24 Antigen ............................................. SI Phenotype ............................................ CD4+ T CELLS ............................................

19 19 19 19 19 20

CELL SURFACE ACTIVATION MARKERS ............................................ CORRELATION BETWEEN SERUM AND LYMPHOID PHENOTYPIC ANTIGENS ...................e21 DISCUSSION .................................................................... 21 REFERENCES ............ ....22 .................

INTRODUCTION Initial infection with human immunodeficiency virus (HIV) is followed by an asymptomatic period of variable duration characterized by low or absent virus replication, stable or slowly decreasing numbers of CD4+ T-helper cells, and qualitative defects in T-cell function (48). The pathogenesis of HIV infection involves dynamic interactions between the virus and the host immune system which result in immune activation throughout the course of infection. The degree of activation of the immune system can be monitored by measuring the serum levels of a variety of molecules such as 02-microglobulin (132-M) and neopterin as well as other serum and cellular markers that correlate with clinical progression of HIV disease (51, 78, 122). Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management.

The various phases of HIV infection, including the early asymptomatic phase, are closely associated with quantifiable laboratory findings (48, 51, 78, 110, 122). For example, immune dysfunction in advanced disease is clearly related to the profound depletion of helper T cells, as well as to an increase in HIV antigenemia and viremia (26, 144). Surrogate markers of HIV infection are, by definition, measurable traits that correlate with development of clinical AIDS. Although several candidate markers have been described, only a few have shown promise. Ideally, assessment of these markers should fulfill the following criteria: (i) permit identification of patients at highest risk of disease progression, (ii) aid in estimating the duration of infection, (iii) assist in disease staging, (iv) predict development of indicator diseases (opportunistic infections of AIDS), and (v) follow, in vitro, the therapeutic efficacy of immunomodulating or antiviral treatments. In addition, these markers must be easily quantifiable, reliable, clinically available, and affordable. The most characteristic feature of AIDS is a selective depletion of the CD4+ T-helper-inducer subset of T cells. The degree of CD4+ T-cell depletion is currently the single most important laboratory finding taken into consideration

* Corresponding author. Mailing address: Montreal General Hospital, 1650 Cedar Ave., Room B7-117, Montreal, Quebec, Canada H3G 1A4. Phone: (514) 934-8035. Fax: (514) 937-1424.

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TABLE 1. Surrogate markers for early and late stages of HIV disease progression Disease phase

Type of marker

Mechanism

Early (immunocompetent phase)

Immune activation Cellular immune activation markers

Host dependent HLA-DR+ T cells IL-2R+ T cells

02-M

Serum immune activation markers

Neopterin sCD8 sIL-2R

Anti-gp120 Anti-p24 IgA

Antibody upregulation

Late (immunodeficient phase)

Virus dependent CD4+ T cells

Immune dysfunction

Cellular immune dysfunction marker

IFN

Cytokine depletion

IL-2

Anti-p24 Anti-gp120

Antibody downregulation

when recommendations are made regarding therapy with antiretroviral drugs. Most experimental therapeutic protocols enroll patients on the basis of CD4+ T-cell counts and/or the presence or absence of viral antigenemia. These surrogate markers of clinical AIDS development are used to formulate decisions on the timing of medical intervention, to predict actuarial outcomes, and to plan future health care expenditures. This review will examine the current state of knowledge and the clinical usefulness and role of surrogate markers in the natural history and treatment of HIV infection. PATHOPHYSIOLOGY

Large prospective studies on the natural history of HIV infection have provided insight into the pathophysiology of this illness (48, 70, 111, 193). Table 1 lists, for the early (immunocompetent) and the late (immunodeficient) phases of HIV-related disease, the types of markers that are useful for monitoring progression of HIV infection. Early in infection, numbers of leukocytes, lymphocytes, and T cells are normal. However, numbers and percentages of T-cell subsets begin to change soon after seroconversion. Levels of CD8+ T cells rise dramatically upon infection with HIV (111). These may represent cytotoxic T cells attempting to control HIV infection. Initiation of HIV infection is characterized by immune system priming and activation of immune effector cells. T cells become activated and express increased levels of interleukin-2 receptor (IL-2R) and major histocompatibility complex-encoded HLA-DR antigens (12, 151). Soluble molecules secreted by activated T cells and antibodies specific for the envelope and core proteins of HIV are also found in greater concentrations in the sera of recently HIV-infected individuals (6, 150). The late stage of infection immediately preceding development of clinical AIDS is characterized by alterations in cytokine production, a marked decrease in the ability to respond to neoantigens (110), and a decline in numbers of CD4+ T cells (110). Antigenemia and viremia are also found and are indicative of viral replication.

SEROLOGIC T-CELL ACTIVATION MARKERS

02-M 12-M is a low-molecular-weight (11,800) polypeptide that forms the light chain of the class I major histocompatibility complex antigens present on the surface of most nucleated cells (91). P2-M is also present in most biologic fluids at low concentrations and can be measured by using commercially available quantitative competitive immunoassays such as enzyme-linked immunosorbent assays (ELISA) or competitive radioimmunoassays. It is a nonspecific but relatively sensitive marker for immune activation. In 1982, early in the AIDS epidemic, increased P2-M was reported in the sera of homosexual men with AIDS (25, 72, 176). At that time, AIDS was diagnosed solely by clinical presentation, although laboratory abnormalities were used to support the diagnosis in suspected cases. The major problem faced by physicians was how to recognize asymptomatic or subclinical disease prior to the manifestation of opportunistic infections or Kaposi's sarcoma. Since HIV was not yet identified as the infectious agent causing AIDS, surrogate markers of clinical disease development were of particular interest and were an important area of investigation. In one early study, elevated serum j2-M clearly identified homosexual and drug-abusing men with AIDS or suspected AIDS and suggested that quantitation of j2-M could have diagnostic value in the screening of high-risk groups for AIDS (207). In two groups of homosexual men evaluated prospectively in 1983 and 1985, serum 132-M was elevated in 64% of HIV-infected individuals but in only 6.7% of uninfected controls (103). Serum P2-M levels of >3.0 mg/liter in the HIV-infected group were associated with progression to AIDS. High levels of 12-M have also been reported in patients with various viral diseases, including those infected with cytomegalovirus, as well as in patients with lymphoproliferative disorders such as lymphomas (56). Since these two disease states may be present in late-stage HIV infection, it is important to interpret the data on serum 32-M levels in the

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context of the total clinical picture. Elevated serum 2-M has been noted in certain uninfected individuals in high-risk groups for AIDS such as hemophiliacs and drug abusers (23, 58, 153, 165). In these groups, abnormally high serum 132-M levels correlated well with increased transaminases and underlying chronic hepatitis rather than intravenous use of factor concentrates or drugs. The results from several longitudinal studies of high-risk groups have also demonstrated that 12-M is an early marker of HIV infection. Serum concentrations above background levels are detected in most infected individuals within 6 months of seroconversion (13, 14, 51, 75, 76, 78). Those with high (or low) levels of 032-M at the end of 1 year tend to have high (or low) levels for several years. While the magnitude of CD4+ T-cell decline does not correlate with the rise in t32-M levels in the first year, 2 to 3 years after seroconversion 132-M levels that were increased initially did correlate inversely with the rate of decline of CD4+ T-cells (75). Elevated levels of 12-M in male homosexuals were the single most powerful predictor of progression to AIDS in a European cohort study, the Multicenter AIDS Cohort Study in Los Angeles, and the San Francisco General Hospital cohort study (131). Production of 32-M is stimulated by HIV infection, and its measurement may be useful in evaluating antiviral therapy (11, 87). Zidovudine (AZT), administered to patients with AIDS or AIDS-related complex (ARC), appeared to decrease serum 12-M levels after 8 to 12 weeks of treatment (86, 87). This decline was not sustained, however, and levels returned to baseline pretreatment levels by 6 months (12, 86,

87). The usefulness of serum 32-M levels as a marker of disease progression has been studied in several bodily fluids and in various high-risk groups. The ratio of cerebrospinal fluid (CSF) "2-M/serum 12-M may be of some use as a marker for HIV-associated neurologic complications and appears superior in this regard to CSF ,B2-M concentration alone (82). Recently, a study found 132-M in the CSF of patients with AIDS dementia complex (20, 47). Serum 12-M levels were higher in HIV-infected than in uninfected pregnant women. These levels were directly related to HIV status and not to pregnancy or month of gestation (109). In early-stage, vertically acquired, perinatal HIV infection, infants do not always exhibit CD4+ T-cell depletion at 6 months of age. Most, however, have elevated serum 32-M levels. Those with the highest levels are more likely to progress to clinical AIDS (43, 194). Although no ethnic, sex, or racial differences were noted among HIV-seronegative intravenous drug abusers, significantly higher levels of serum 2-M are observed in HIV-infected white compared with black intravenous drug abusers despite similar CD4+ T-cell counts (197). Neopterin

Neopterin (6-D-erythro-trihydroxypropylpterin) is a product of GTP catabolism that is derived from macrophages and B cells stimulated with gamma interferon (IFN--y) (64, 80). Neopterin is present in both urine and serum (201). Reverse-

phase high-performance liquid chromatography is used to determine urinary concentration (189). There is a commercially available radioimmunoassay kit for measuring levels of neopterin in serum, plasma, and CSF (61). Before the AIDS epidemic, high neopterin levels in serum or urine were only found in patients with atypical phenylketonuria, a congenital deficiency of phenylalanine hydroxylation (46). Elevated neopterin levels have also been re-

ported in conditions that involve rapid cellular turnover and activation of the immune system (80, 135). Patients receiving biological response modifiers such as IFN-a, IFN-y, IL-2, or tumor necrosis factor alpha (TNF-a) exhibit high serum neopterin levels. Neopterin production increases in numerous infectious and inflammatory disorders, including viral, bacterial, and fungal infections; aseptic meningoencephalitis; kidney graft rejection; acute graft-versus-host disease; and collagen vascular diseases, and in the advanced stages of certain malignancies (81, 136). The function of neopterin is unknown. AIDS and ARC patients can be easily distinguished from seronegative individuals on the basis of urine and serum neopterin measurements (1, 8, 19, 21, 35, 51, 59, 60, 62-64, 166, 201). Urine and serum neopterin levels are also elevated in patients with HIV-related persistent generalized lymphadenopathy and in asymptomatic HIV-infected individuals. Therefore, an elevated urine or serum neopterin level appears to be a very early marker of HIV infection (96, 106, 107, 155, 156). Longitudinal studies have revealed that neopterin levels correlate with disease progression (51, 65, 78, 98-101, 122). The Multicenter AIDS Cohort Study reported serum neopterin level to be the strongest predictor of progression to clinical AIDS. Serum neopterin level predicted not only disease progression but also the rate of CD4+ T-cell decline as early as 3 years in advance (51, 78, 122). Similar to P2-M levels, neopterin levels are stimulated by HIV infection. Therefore, measurement of neopterin may be useful in evaluating antiviral therapy (11, 87). The mean level of serum neopterin in patients on AZT decreased at 4 weeks (from a mean pretreatment level of 15.76 nmol/iter to a mean of 12.73 nmol/liter at 4 weeks; P < 0.001). The maximum reduction was seen at 8 weeks (10.78 nmol/liter). Thereafter, mean values increased but remained below the pretreatment value for more than 1 year (12). Neopterin levels in blood and CSF are also elevated in patients with HIV-associated neurologic complications, perhaps reflecting the activation of macrophages within the central nervous system (178). It is as yet unclear what predictive value neopterin measurements may have in seropositive pregnant women or in perinatally acquired childhood HIV infection. sIL-2R

High-affinity IL-2R is composed of two different IL-2binding peptides; IL-2Ra (55 kDa) and IL-2R1 (75 kDa). Soluble IL-2R (sIL-2R) can be measured in serum with a sandwich ELISA or a competitive radioimmunoassay (79, 186). Following activation of T cells by antigen or mitogens, IL-2Ra, also known as Tac peptide, is released into the supernatant of cells cultured in vitro. Elevated serum levels of IL-2Ra are also detected in vivo in clinical conditions associated with lymphocyte activation such as adult T-cell and hairy-cell leukemias, acute and chronic lymphocytic leukemias, rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, multiple sclerosis, and some viral infections (160). IL-2 or T-cell growth factor is a lymphokine secreted by activated T cells. This lymphokine interacts with specific high-affinity IL-2R on the surface of other activated T cells. sIL-2R is derived from these activated T cells. Since T-cell activation may amplify HIV replication, identification of individuals with high levels of sIL-2R may be important prognostically (77, 79, 84).

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One-half of HIV-infected individuals had elevated serum levels of sIL-2R compared with seronegative controls (151). An inverse relationship was noted between sIL-2R levels and CD4+ T-cell counts. In another study, 73% of patients with AIDS, 80% of those with ARC, and 75 to 85% of asymptomatic HIV-infected individuals had elevated sIL-2R levels (95). sIL-2R levels reflected AIDS Centers for Disease Control (CDC) classification status and correlated negatively with CD4+ T-cell numbers, lymphocyte count, and CD4+/ CD8+ T-cell ratios but not with leukocyte or B-cell counts (79). The highest levels of sIL-2R were found in patients with 289 U/ml). Significant CDC group IVD disease (1,006 differences were noted between CDC classification groupings as well as between uninfected and infected individuals (asymptomatic HIV-infected versus uninfected patients [210 149 versus 74 24 U/ml; P < 0.001]). In this study, it appeared that elevated sIL-2R levels in AIDS patients were not the result of secretion of the receptor from cells but rather were due to destruction of either activated T cells or CD4+ T-cells (79). Whether sIL-2R measurement will become useful in predicting disease progression remains to be determined. Large cohort studies to determine the usefulness of sIL-2R quantitation in biological fluids as a surrogate marker for clinical AIDS development have yet to be carried out. ±

±

±

sCD8 Soluble CD8 (sCD8) is a secreted form of the antigen expressed by CD8+ T lymphocytes. sCD8 serum levels can be measured by a sandwich-type ELISA (137). sCD8 appears to be released in response to lymphocyte activation, and its measurement may be useful in quantitating the degree of CD8+ T-cell involvement in pathologic events (188, 205). Levels of circulating sCD8 have been examined in all stages of HIV infection and found to be an early marker for HIV infection preceding the appearance of anti-HIV-specific antibodies (205). The level of sCD8 correlates with the number of circulating CD8+ and CD8+CD38+ T lymphocytes. Individuals with HIV-associated neurologic disease also have elevated levels of serum as well as CSF sCD8 (67). SEROLOGIC B-CELL ACTIVATION MARKERS IgG, IgM, and IgA Functional abnormalities of B cells in AIDS patients, including polyclonal B-cell activation, hypergammaglobulinemia, and raised titers of antibodies to various pathogens and autoantigens, were documented early in the AIDS epidemic (4). Serum immunoglobulin (Ig) concentrations also increase in asymptomatic HIV infection. IgM class anti-p24-specific antibodies are noted 16 to 122 days after seroconversion, and IgG class anti-HIV-specific antibodies arise 18 to 144 days after seroconversion (37, 89). Spontaneous secretion of immunoglobulins of various classes tends to correlate negatively with the percentage, but not the absolute number, of CD4+ T-cells (126). In late-stage HIV infection, serum concentrations of immunoglobulins may decrease. HIV-infected individuals have a relative or an absolute lack of IgG2 and IgG4 (7). The IgG2 subclass appears to be significantly decreased in AIDS patients with pyogenic infections (143). It is unclear whether elevated IgG and IgM levels have prognostic significance in HIV infection. Although elevated serum IgA values have been observed in AIDS patients, generally they are not increased early in

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HIV infection (53, 55, 92, 174). Elevated levels may reflect an immune response to HIV or opportunistic pathogens or to a loss of immunoregulatory control of IgA production. Large cohort studies such as the Vancouver Lymphadenopathy Study of gay men (169, 170), the Toronto Sexual Contact Study (31), the Canadian National Hemophilia Immune Study (193), and the U.S. Air Force study (55) have noted an association between elevated IgA levels and subsequent progression to disease. CICs The humoral response to HIV infection results in the production of high levels of circulating immune complexes (CICs). Several cross-sectional studies have noted an increased prevalence of CICs in HIV-infected individuals (73, 119, 203). Using an assay based on complement componentspecific Clq monoclonal antibody coupled to a solid phase to capture CICs from sera, the Vancouver Lymphadenopathy Study noted higher levels of CICs in men who progressed to AIDS (169, 170), while the San Francisco Men's Health Study did not find that elevated CICs were an indication of disease progression (163). ANTIBODIES TO HIV HIV-specific antibodies are produced early in the course of infection. Low serum titers of neutralizing antibody are observed as part of the humoral response to this virus. The antibodies that are formed are directed against all of the major gene products: env products gpl20 and gp41; pol products p66, p51, and p33; and gag products p55, p24, p18, and p15. Studies of antibody response in early infection, using numerous antibody assay systems including ELISA, indirect immunofluorescence assays, radioimmunoprecipitation, and Western blotting (immunoblotting), have shown a clear difference in test sensitivities (44, 45, 152). The earliest antibody response is directed against gp160 and is followed shortly by antibodies directed against p24 (66). Since the first diagnostic test for HIV was licensed by the U.S. Food and Drug Administration for screening of sera, attempts to identify specific antibody profiles associated with disease stage have been sought (139, 153). Anti-p24 Progression to AIDS is often associated with a decline in anti-HIV serum antibody titers, particularly anti-p24 core protein antibodies (114, 172). A decline in anti-p24 antibodies precedes p24 antigenemia and correlates with a poor prognosis in HIV-infected individuals (17, 18, 57, 114, 200). In a 4-year prospective study of British HIV-infected individuals, those with no anti-p24 antibodies or those with declining levels of anti-p24 antibodies had the worst prognosis (200). This was apparent as early as 27 months prior to the diagnosis of AIDS. This study did not find any association between the presence of anti-gp4l and anti-gpl20 antibodies and clinical outcome (200), nor was any decrease detected in the titers of these antibodies with time. Neutralizing antibody titers were unrelated to anti-p24 antibody titers. Therefore, the protective effect of high anti-p24 levels was surmised not to be mediated through a neutralizing mechanism (200). The humoral response to p24 detected at seroconversion is associated with clinical outcome (27, 52). Patients with an

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initial low-titer antibody response to p24 have a faster rate of progression to CDC stage IV disease than those with a high-titer anti-p24 response, who progress to AIDS more slowly (27, 52). This finding is similar to conclusions drawn from another study in which anti-p24 antibody titers (used as a marker for HIV-specific immune response) were measured at entry in a cohort of homosexual men who were monitored prospectively for AIDS development for 54 months (175). Individuals with low anti-p24 antibody titers had an incidence of AIDS of 34% over 54 months. Persons with low anti-p24 antibody levels and high serum neopterin levels had an incidence of AIDS of 60% over 54 months (175).

Anti-gpl20 Antibody responses to HIV in hemophiliacs revealed a strong association between the absence of anti-gp120 antibodies and progression to clinical ARC such that anti-gpl20 antibody levels may be of possible prognostic value (29). However, this association was evident only when antibodies were screened by Western blotting of proteins separated under reducing conditions, a procedure not commonly used for screening sera from AIDS patients. Approximately 70% of HIV-infected pregnant women do not transmit infection vertically to their offspring (195). The lack of vertical transmission is correlated in some studies with the presence of neutralizing antibodies against the V3 hypervariable loop of gpl20 (40, 71), and in another study it is correlated with high levels of neutralizing antibody specific for gpl20 epitopes not involved in CD4 binding (195).

Anti-p17 In a small Dutch study of gay men, anti-p17 reactivity was detected as early as 10 months prior to disease development and preceded anti-p24 decline (113). Anti-p17 antibodies have some virus-neutralizing activity, and declining titers of anti-p17 may signify reduced control of HIV pathogenesis.

Anti-gp4l The HIV envelope protein, gp4l, has sequence homology with pl5E, a peptide derived from a C-type retrovirus that has immunosuppressive properties. It was postulated that the presence of antibodies to pHIVIS, a 17-mer putative immunosuppressive peptide derived from gp41, could neutralize the immunosuppression mediated by this peptide and thus affect the outcome of HIV disease and development of AIDS (30). Two studies of homosexual men failed to find any association between antibodies to pHIVIS and HIV disease progression (28, 112). Antibodies to gp4l may be important in preventing vertical transmission of HIV infection to neonates (195). Anti-NEF Accessory gene products of HIV such as negative factor (NEF) are also antigenic. This protein may play a role in regulating the expression of viral structural proteins. Absent or transient responses to NEF were associated with absence or disappearance of anti-p24 core protein antibodies, reappearance of HIV core antigen, and decline in CD4+ T-cell numbers (158, 159). The association of low or absent levels of anti-NEF antibody with poor prognostic marker profiles suggested a correlation between anti-NEF-specific antibody responses and disease progression. Closer examination re-

CLIN. MICROBIOL. REV.

vealed that this association was not significant. Anti-NEF antibodies are detected in groups at no risk of HIV infection (154). When a sensitive liquid-phase radioimmunoassay was used to examine serial serum samples from 12 individuals following seroconversion and 32 HIV-infected hemophiliacs, anti-NEF antibodies were undetectable independent of the appearance of anti-gag, anti-pol, or anti-env specific antibodies (10). OTHER ANTIBODIES There is now evidence that the HIV virus induces a wide range of autoantibodies and autoimmune phenomena (130).

Lupus Anticoagulant and Anticardiolipin Elevated levels of lupus anticoagulant and anticardiolipin antibodies have been observed in HIV-infected individuals in high-risk groups (16, 142). Although these antibodies were originally thought to be early autoantibodies, they most likely represent an antiphospholipid-specific response to viral infection in general and do not have any prognostic value or significance (33, 34, 83).

Antileukocyte Antibodies Immune thrombocytopenia purpura (ITP) is a major hematologic abnormality found in those infected with HIV-1 and has been described in all risk groups for HIV disease: homosexual men (88, 93, 129), hemophiliacs (50, 93), and intravenous drug users (93, 167). ITP has been observed in 10 to 20% of asymptomatic people infected with HIV and in 25 to 45% of AIDS patients (93, 199). The syndrome is clinically indistinguishable from classic autoimmune thrombocytopenia purpura with respect to elevated numbers of bone marrow megakaryocytes, peripheral destruction of antibody-coated platelets, absence of antinuclear antibodies, and response to treatment such as administration of prednisone or splenectomy. HIV-associated ITP is different from classic ITP in that there is a marked increase in plateletassociated IgG and complement components C3 and C4 and CICs (93). The mechanism of HIV-associated ITP is thought to be nonspecific deposition of CICs and complement on platelets (92, 93, 129, 206) and/or a specific antiplatelet antibody to a platelet antigen of 25,000 Da (182). Although bone marrow stem cell damage by HIV-1 is also a possible mechanism, most reports demonstrate either normal or elevated levels of bone marrow megakaryocytes (93, 145, 168). Immune neutropenia may, to a certain degree, be accounted for by a similar mechanism (94). Antilymphocyte antibodies are found in some, but not all, HIV-infected individuals and have no prognostic significance (94, 141,

183). Anti-sCD4 The CD4 molecule has been identified as the cellular receptor for HIV. An important mechanism by which HIV induces immunodeficiency is through the selective loss and functional impairment of CD4+ T cells. Autoantibodies to sCD4 have been observed in 5 to 20% of HIV-infected patients at various stages of disease but not in uninfected individuals (173, 187, 202). No correlation was noted between presence of anti-sCD4 antibodies and number of circulating CD4+ T cells or CD4+/CD8+ T-cell ratio (173, 187, 202).

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OTHER SEROLOGIC MARKERS

TNF TNF-a functions as part of a complex network of cytokines involved in the regulation of the immune system (9). TNF-a is produced by macrophages and monocytes in response to naturally occurring infections and generally upregulates macrophage and cytotoxic T-cell potential (124, 177). Elevated levels of TNF-a have been found in sera of AIDS patients but not in sera of patients in the early stages of HIV infection (104, 125, 155-157, 162, 204). TNF-a may be responsible for myelin damage that occurs in HIVassociated encephalopathy (125) and may serve as a surrogate marker for monitoring the neurologic manifestations of this disease. The role of TNF-a in the pathogenesis of HIV infection is unclear. New immunoassays are currently being used to screen longitudinally sera collected from cohort studies. These studies could provide insight into the potential usefulness of this marker.

Acid-Labile Human Leukocyte EFN and 2-5A Synthetase Acid-labile human leukocyte IFN-a and levels of 2-5A synthetase, an IFN-induced enzyme, are elevated in homosexual men infected with HIV (31, 32, 39). In the Toronto Sexual Contact Study, acid-labile IFN-a and 2-5A synthetase levels correlated with cervical lymphadenopathy and progression to AIDS (115). IFN-a present in AIDS patient sera can induce the expression of TNF-a receptors on peripheral blood monocytes from HIV-infected patients. IFN-a is present in greater amounts in later stages of disease. This activation of the TNF system may contribute to some of the physiological disturbances observed in AIDS patients (115). ANTIGEN MARKERS

p24 Antigen The HIV-encoded gag gene product, p24, is one of the first virally encoded molecules detectable in the circulation of infected individuals. This antigen is transiently present following the initial infection with HIV and reappears late in the disease (36). Few patients have persistent p24 antigenemia. Although p24 antigenemia may be a poor prognostic sign, many patients do not develop AIDS for several years following detection of circulating p24 (85, 121, 132). Long-term AZT therapy may prolong survival and decrease the frequency of opportunistic infections, in particular, episodes of Pneumocystis carinii pneumonia (54, 138, 164). AZT treatment reduces circulating levels of p24 antigen, indicating that measurement of this marker may be useful in evaluating new antiretroviral drugs (140, 179). However, one study reported that improvement in CD4+ T-cell numbers and the level of p24 antigenemia following AZT treatment did not predict outcome in AIDS patients who previously had P. carinni pneumonia (180). Numerous epidemiologic studies have shown a clear correlation between falling CD4+ T-cell numbers and development of AIDS. Decline in CD4+ numbers appears to reflect an increase in HIV replication by correlation with increased serum concentrations of p24 antigen (42, 43). In a study of predictive markers of AIDS in hemophiliacs, both p24 antigenemia and low CD4+ T-cell counts were very strong independent predictors of disease progression (49, 131).

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Seventeen percent of seropositive hemophiliacs have detectable serum p24 antigen (49, 116, 117). The 2-year actuarial incidence of AIDS was 24% after detection of p24 antigen, 16% after the loss of anti-p24 antibody, 20% after the loss of anti-gp120 antibody, 31% after a decline of CD4+ T-cell counts to less than 200/mm3, and 67% for those patients who were positive for p24 antigen and whose CD4+ T-cell counts fell below 200/mm3 (49). Although the presence of serum p24 antigen alone was highly specific for AIDS, the sensitivity of p24 detection was low. When the presence of serum p24 antigen was coupled with a low CD4+ T-cell count, the specificity increased to almost 100%, but the sensitivity of these tests as predictive markers for AIDS fell to as low as 25%. Results obtained from this study of American patients with hemophilia were in agreement with those of other published studies of hemophiliacs or homosexual men in noting that p24 antigenemia and CD4+ T-cell numbers were independently predictive of progression to AIDS (42, 43, 131, 161). Patients with p24 antigenemia and very low CD4+ T-cell numbers had a high risk of developing AIDS, approximately 50% within 1 year and 67% within 2 years (49). These data were in contrast to those of a French study of patients with hemophilia in which p24 antigenemia, but not CD4+ T-cell counts, had predictive value (3). In a large multicenter prospective cohort study of 1,219 patients with hemophilia and related disorders, the 8-year mean cumulative rates for progression to AIDS were 13% for ages 1 to 17, 28% for ages 18 to 34, and 44% for ages 35 to 70. The presence of elevated IFN-a, elevated serum p24 antigen, low or absent anti-p24 antibodies, and low or absent anti-gp120 antibodies all had predictive value for the development of AIDS (70, 144). Adults older than 35 years had a higher incidence of low CD4+ T-cell counts than younger subjects, whereas adolescents with low anti-p24 antibody levels had the lowest incidence of AIDS (70, 147).

SI Phenotype Syncytium-inducing (SI) capacity is a biological property of certain HIV isolates. The prevalence of such phenotypic variants appears to be related to the stage of HIV infection. Non-SI-inducing isolates are detected throughout HIV infection, whereas SI isolates are observed later during the course of infection, often prior to AIDS diagnosis (97). Individuals with SI HIV variants have lower CD4+ T-cell counts than those without such variants (97). SI variants emerge an average of 2 years before progression to AIDS and predict a significantly increased rate of CD4+ T-cell loss (97).

CD4+ T CELLS Technological advances of the early 1980s and the development of commercially available monoclonal antibodies directed against specific lymphocyte cell surface antigens have led to a better understanding of immunodeficiency and lymphoproliferative disorders, diseases known to be associated with abnormal lymphocyte populations. The diagnosis and management of many of these disorders depend on serial monitoring of cell populations. The most useful assay in determining the level of immunodysfunction in HIV infection is the phenotypic analysis of the patient's lymphocytes, since this virus targets and destroys CD4+ T cells (133). Early in the AIDS epidemic, prior to the identification of HIV as the pathogenic agent, persons thought to be at risk for AIDS were screened by determining the "helper/suppressor ratio," or CD4+/CD8+ T-cell ratio. Low values

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(below 1.0) in high-risk individuals raised suspicion of immunodeficiency. The identification of HIV as the causative agent of AIDS and the subsequent demonstration that CD4 can bind the envelope of HIV (gpl20) confirmed the importance of CD4+ T cells as targets of this virus (120). It became clear, from data accumulated from most large cohort studies, that the severity of HIV-induced disease was associated with progressive depletion of both the percentage and absolute numbers of CD4+ T cells and that these cellular markers were powerful and independent predictors of progression to AIDS (51, 131). The percentage of CD4+ T cells, absolute CD4+ T-cell numbers, and the CD4+/CD8+ T-cell ratio all have excellent prognostic value for development of clinical AIDS and are highly correlated (26, 134, 181, 184, 185). The CDC suggests the following equivalence values between absolute numbers of CD4+ T cells and the percentage of lymphocytes that are CD4+ T cells: >500 CD4+ T cells per pl is similar to >29% of lymphocytes being CD4+ T cells, 200 to 499 CD4+ cells per ,ul is similar to 14 to 28% CD4+ T cells, and 20 to 25% (26, 118, 148). This information can be used to formulate decisions on prophylactic treatment of individuals at high risk for P. carinii pneumonia. Uninfected individuals tend to have a baseline level of CD4+ T cells that is maintained over time, with minor fluctuations. As early as 6 months following seroconversion, CD4+ T-cell numbers decline (22, 170). Within 2 years, baseline levels of CD4+ T cells decrease by 30 to 50% (108). Many asymptomatic HIV-infected persons maintain stable levels of approximately 600 cells per mm3 for many years (108). Some cohort studies, however, have demonstrated slow yet steady declines in CD4+ T-cell numbers even during the clinically stable latent period (111). Healthy asymptomatic individuals without p24 antigenemia and mean CD4+ T-cell counts of approximately 520/mm3 can exhibit declines of 5 to 6 CD4+ T cells per mm3 per month (192). Rapid loss of CD4+ T-cell numbers is a poor prognostic sign and may herald the development of opportunistic infections (134). Following the diagnosis of AIDS, CD4+ T-cell counts remain very low and can decline to undetectable levels prior to death. In a British study of hemophiliacs, patients with CD4+ T-cell counts of 200/mm3 had a 5% cumulative risk of developing AIDS. This probability increased dramatically to

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50% when counts fell to 50 cells per mm3 and 81% when they dropped to 10 cells per mm3 (116, 146). Clinically beneficial effects of AZT have been demonstrated in those with AIDS and ARC as well as in asymptomatic individuals with CD4+ T-cell counts of serum level of neopterin or 12-M > serum level of IgA > sIL-2R > p24 antigen (51). The level of CD4+ T cells in

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combination with serum level of either neopterin or 32-M was the most powerful predictor of progression to AIDS

(51). CD4+ T-cell counts and 32-M, neopterin, and p24 antigen levels are now measured in clinics and used singly or in combination to monitor patients and make therapeutic decisions such as when to begin antiretroviral therapy or prophylaxis for P. cannii pneumonia (6, 51, 52, 54, 87, 98-101, 138). If these markers are to be used as primary endpoints in clinical studies, issues such as standardization of tests must be addressed. Consensus must be sought for methods, reagents, and equipment. In conclusion, direct assessment of immune deficiency status through measurement of CD4+ T-cell percent or absolute numbers will continue to be the preferred surrogate marker of clinical AIDS development in the near future because this test is widely available, affordable, and well understood. The usefulness of indirect measures of disease activity such as 02-M, neopterin, and sCD8 markers as well as direct measures of virus activity such as viremia as endpoints in clinical trials is less well established. The goal of large-scale longitudinal studies is to estimate the value and practicality of monitoring these indirect and direct measures of disease activity as additional surrogate markers for HIV disease progression. REFERENCES 1. Abita, J. P., H. Cost, S. Milstien, S. Kaufman, and G. Saimot. 1985. Urinary neopterin and biopterin levels in patients with AIDS and AIDS-related complex. Lancet ii:51-52. 2. Aboulker, J.-P., and A. M. Swart. 1993. Preliminary analysis of Concorde trial. Lancet 341:889-890. 3. Allain, J. P., Y. Laurian, D. A. Paul, F. Verroust, M. Leuther, C. Gazengel, D. Senn, M.-J. Larrieu, and C. Bosser. 1987. Long-term evaluation of HIV antigen and antibodies to P25 and GP41 in patients with hemophilia. Potential clinical importance. N. Engl. J. Med. 317:1114-1121. 4. Amadori, A., and L. Chieco-Bianchi. 1990. B-cell activation in HIV-infection: deeds and misdeeds. Immunol. Today 11:374379. 5. American Foundation for AIDS Research. 1990. AIDS/HIV treatment directory, vol. 4. American Foundation for AIDS Research, New York. 6. Anderson, R. E., W. Lang, S. Shiboski, R. Royce, N. Jewell, and W. Winkelstein. 1990. Use of 12 microglobulin level and CD4 lymphocyte count to predict development of acquired immunodeficiency syndrome in persons with human immunodeficiency virus infection. Arch. Intern. Med. 150:73-77. 7. Aucoutrier, P., L. J. Couderc, D. Gouet, F. Danon, J. Gombert, S. Matheron, A. G. Saimot, J. P. Clauvel, and J. L. Preud'homme. 1986. Serum immunoglobulin G dysbalances in lymphadenopathy syndrome and acquired immunodeficiency syndrome. Clin. Exp. Immunol. 63:234-240. 8. Bagasra, O., J. W. Fitzharris, and T. R. Bagasra. 1988. Neopterin: an early marker of development of pre-AIDS conditions in HIV seropositive individuals. Clin. Immunol. Newsl. 9:197-199. 9. Balkwill, F. R., and F. Burke. 1989. The cytokine network. Immunol. Today 10:299-304. 10. Barhaoui, E., A. Benjouad, J. M. Sabatier, J. P. Allain, Y. Laurian, L. Montaignier, and J. C. Gluckman. 1990. Relevance of anti-nef antibody detection as an early serologic marker of human immunodeficiency virus infection. Blood 76:257-264. 11. Bass, H. Z., W. D. Hardy, R. T. Mitsuyasu, J. M. G. Taylor, H. X. Wang, M. A. Fischl, S. A. Spector, and J. L. Fahey. 1992. The effect of zidovudine treatment on serum neopterin and 12-microglobulin levels in mildly symptomatic human immunodeficiency virus type-1 (HIV-I) seropositive individuals. J. Acquired Immune Defic. Syndr. 5:215-221. 12. Bass, H. Z., P. Nishanian, W. D. Hardy, R. T. Mitsuyasu, E.

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infection. AIDS 4:251-253. 29. Chou, M.-J., T.-H. Lee, A. Hatzakis, T. Mandalaki, M. F. McLane, and M. Essex. 1988. Antibody responses in early human immunodeficiency virus type I infection in hemophiliacs. J. Infect. Dis. 157:805-811. 30. Cianciolo, G., H. Bogerd, and R. Snyderman. 1988. Human retrovirus-related synthetic peptides inhibit T-lymphocyte proliferation. Immunol. Lett. 19:7-14. 31. Coates, R. A., V. T. Farewell, J. Raboud, S. E. Read, M. Klein, D. MacFadden, L. M. Calzavara, J. K. Johnson, M. M. Fanning, and F. A. Shepherd. 1992. Using serial observations to identify predictors of progression to AIDS in the Toronto Sexual Contact Study. J. Clin. Epidemiol. 45:245-253. 32. Coates, R. A., S. E. Read, M. M. Fanning, H. Vellend, F. A. Shepherd, and J. K. Johnson. 1986. The relationship between 2-5A synthetase levels and persistent lymphadenopathy in homosexual men with antibodies to HTLV-III. Clin. Invest. Med. 9:59-64. 33. Cohen, A. J., T. M. Philips, and C. M. Kessler. 1986. Circulating coagulation inhibitors in the acquired immunodeficiency syndrome. Ann. Intern. Med. 104:175-180. 34. Cohen, H., I. J. Mackie, N. Anagnostopoulos, G. F. Savage, and S. J. Machin. 1989. Lupus anticoagulant, anticardiolipin antibodies, and human immunodeficiency virus in haemophilia. J. Clin. Pathol. 42:629-633. 35. Cooke, R. A. 1989. Neopterin and alpha and beta interleukin-1 levels in sera of patients with human immunodeficiency virus infection. J. Clin. Microbiol. 27:1919-1923. 36. Coombs, R. W., A. C. Collier, J. P. Allain, B. Nikora, M. Leuther, G. F. Gjerset, and L. Corey. 1989. Plasma viremia in human immunodeficiency virus infection. N. Engl. J. Med. 321:1626-1631. 37. Cooper, D. A., J. Gold, P. MacLean, B. Donovan, F. Finlayson, T. Barnes, H. M. Michelmore, P. Brooke, and R. Penny. 1985. Acute AIDS retrovirus infection: definition of a clinical illness associated with seroconversion. Lancet i:537-540. 38. De Paoli, P., A. Carbone, S. Battistin, M. Crovatto, N. Arreghini, and G. Santini. 1987. Selective depletion of the OKT 4+ 4B4+ subset in lymph nodes from HIV+ patients. Immunol. Lett. 16:71-73. 39. De Stefano, E., R. M. Friedman, A. E. Friedman-Kien, J. J. Goedert, D. Henrikson, 0. T. Preble, J. A. Sonnabend, and J. VilceL 1982. Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy. J. Infect. Dis. 146:451-455. 40. Devash, Y., T. A. Calvelli, D. Wood, K. Reagan, and A. Rubinstein. 1990. Vertical transmission of human immunodeficiency virus is correlated with the absence of high affinity/ avidity maternal antibodies to the gpl20 principal neutralizing domain. Proc. Natl. Acad. Sci. USA 87:3445-3449. 41. De Wit, R., P. J. M. Bakker, P. Reiss, F. J. Hoek, J. M. A. Lange, J. Goudsmit, and K. H. N. Veenhof. 1990. Temporary increase in serum 02 microglobulin during treatment with interferon-alpha for AIDS-associated Kaposi's sarcoma. AIDS 4:459-462. 42. De Wolfe, F., J. M. A. Lange, J. T. M. Houwelling, R. A. Coutinho, P. T. Schellekens, J. Van der Noordaa, and J. Goodsmit. 1988. Numbers of CD4+ cells and the levels of core antigens of antibodies to the human immunodeficiency virus as predictors of AIDS among seropositive homosexual men. J. Infect. Dis. 158:615-622. 43. De Wolfe, F., M. Roos, J. M. A. Lange, J. T. M. Houwelling, R. A. Coutinho, J. Van der Noordaa, and J. Goodsmit, et al. 1988. Decline in CD4+ cell numbers reflects increase in HIV-1 replication. AIDS Res. Hum. Retroviruses 4:433-440. 44. dos Santos, J. I., and B. G. Castro. 1989. Comparison of enzyme-linked immunosorbent assays and alternative tests for the detection of HIV antibodies in Brazilian sera. AIDS 3:544-545. 45. dos Santos, J. I., J. C. C. Fernandez, and B. Galvao-Castro. 1989. Specificity of HIV antigen capture assays. AIDS 3:545. 46. Editorial. 1988. Neopterins in clinical medicine. Lancet i:509512.

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47. Elovaara, I., M. livanainen, E. Poutiainen, S. L. Valle, T. Weber, J. Sune, and J. Lahdervirta. 1989. CSF and serum P2 microglobulin in HIV infection related to neurological dysfunction. Acta Neurol. Scand. 79:81-87. 48. El-Sadr, W., M. Mormor, S. Zolla-Pazner, R. E. Stahl, M. Lyden, D. Williams, S. D'Onofrio, S. H. Weiss, and W. C. Saxinger. 1987. Four year prospective study of homosexual men: correlation of immunologic abnormalities, clinical status, and serology to human immunodeficiency virus. J. Infect. Dis. 155:789-793. 49. Eyster, M. E., J. 0. Ballard, M. H. Gail, J. E. Drummond, and J. J. Goegert. 1989. Predictive markers for the acquired immunodeficiency syndrome (AIDS) in hemophiliacs: persistence of P24 antigen and low T4 cell count. Ann. Intern. Med. 110:963969. 50. Eyster, M. E., M. H. Gail, J. 0. Ballard, H. Al-Mondhiry, and J. J. Goedert. 1987. Natural history of human immunodeficiency virus infections in haemophiliacs: effects of T cell subsets, platelet counts and age. Ann. Intern. Med. 107:1-6. 51. Fahey, J. L., J. M. G. Taylor, R. Detels, B. Hofmann, S. Stehn, C. Rinaldo, A. Munoz, L. Schrager, H. Huprikar, N. Graham, and J. M. Phair. 1990. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N. Engl. J. Med. 322:166-172. 52. Farzadegan, H., J. S. Chmiel, N. Okada, L. Ward, L. Poggensee, A. Saah, and J. P. Phair. 1992. Association of antibody to human immunodeficiency virus type 1 core protein (p24), CD4+ lymphocyte number, and AIDS-free time. J. Infect. Dis. 166:1217-1222. 53. Fauci, A. S., A. M. Macher, and D. L. Longo. 1984. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. Ann. Intern. Med. 100: 92-106. 54. Fischl, M. E., D. D. Richman, N. Hansen, A. C. Collier, J. T. Carey, M. F. Para, W. D. Hardy, R. Dolin, W. G. Powderly, J. D. Allan, B. Wong, T. C. Merigan, V. J. McAuliffe, N. E. Hyslop, F. S. Rhame, J. J. Balfour, Jr., S. A. Spector, P. Volberding, C. Pettinelli, and J. Anderson. 1990. The safety and efficacy of zidovudine (AZT) in the treatment of subjects with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann. Intern. Med. 112:727-737. 55. Fling, J. A., J. R. Fischer, R. N. Boswell, and M. J. Reid. 1988. The relationship of serum IgA concentration to human immunodeficiency virus (HIV) infection: a cross-sectional study of HIV-seropositive individuals detected by screening in the United States Air Force. J. Allergy Clin. Immunol. 82:965-970. 56. Forman, D. T. 1982. P2 microglobulin-an immunogenetic marker of inflammatory and malignant origin. Ann. Clin. Lab. Sci. 12:447-452. 57. Forster, S. M., L. M. Osborne, R. Cheingsong-Popov, C. Kenny, R. Burnell, D. J. Jeffries, A. J. Pinching, J. R. W. Harris, and J. N. Weber. 1987. Decline of anti-p24 antibody precedes antigenaemia as correlate of prognosis in HIV-1 infection. AIDS 1:235-240. 58. Franzetti, F., G. Cavalli, C. Uberti Foppa, M. C. Amprimo, P. Gaido, and A. Lazzarin. 1988. Raised serum P2 microglobulin levels in different stages of human immunodeficiency virus infection. J. Clin. Lab. Immunol. 27:133-137. 59. Fuchs, D., E. Artner-Dworzak, A. Hausen, G. Reibnegger, E. R. Werner, G. Werner-Felmayer, M. P. Dierich, and H. Wachter. 1990. Urinary excretion of porphyrins is increased in patients with HIV-1 infection. AIDS 4:341-344. 60. Fuchs, D., M. Banekovich, A. Hausen, J. Hutterer, G. Reibnegger, E. R. Werner, F. D. Gschnait, M. P. Dierich, and D. Wachter. 1988. Neopterin estimation compared with the ratio of T cell subpopulations in person infected with human immunodeficiency virus-1. Clin. Chem. 34:2415-2417. 61. Fuchs, D., F. Chiodi, J. Albert, B. Asjo, L. Hagberg, A. Hausem, G. Norkrans, G. Reibnegger, E. R. Werner, and H. Wachter. 1989. Neopterin concentrations in cerebrospinal fluid and serum of individuals infected with HIV-1. AIDS 3:285288.

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