Human Immunodeficiency Virus (HIV)

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Sep 8, 2000 - Institutes, Watertown, and 6Department of Pediatric Infectious. Disease, Boston Medical Center, Boston, Massachusetts; 7National. Institute of ...
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Human Immunodeficiency Virus (HIV) Type 1 Antibodies in Perinatal HIV-1 Infection: Association with Human HIV-1 Transmission, Infection, and Disease Progression 1

Department of Pediatrics, Division of Infectious Disease, Columbia University College of Physicians and Surgeons, New York, and 2Department of Pediatrics, State University of New York, Brooklyn; 3Abbott Laboratories, North Chicago, and 4Department of Pediatrics, University of Illinois, Chicago; 5New England Research Institutes, Watertown, and 6Department of Pediatric Infectious Disease, Boston Medical Center, Boston, Massachusetts; 7National Institute of Child Health and Human Development, Rockville, Maryland; 8University of Puerto Rico, San Juan; 9Baylor College of Medicine, Texas Children’s Hospital, Houston

Anti –human immunodeficiency virus (HIV) type 1 antibodies in 242 pregnant women and 238 infants were measured at birth and at 1, 2, 4, and 6 months after birth, to estimate their association with perinatal transmission and infant disease progression. Maternal anti–p24 (P p .01) and anti–gp120 (P p .04) antibodies were inversely associated with vertical transmission rates, independent of maternal percentage of CD4 cells, hard drug use, duration of ruptured membranes, serum albumin levels, serum vitamin A levels, and quantitative HIV-1 peripheral mononuclear blood cell culture, but not with maternal plasma immune complex dissociated p24 or HIV-1 RNA copy number, both of which were highly correlated with antibodies. From ages 1–2 months, anti-gp120, -gp41, -p31, and -p66 decayed to a greater extent in infected than in uninfected infants. Infected infants produced anti-p24 antibody by age 2 months, anti-p17 by 4 months, and anti-p41 and anti-gp120 by 6 months. As early as birth, infants with rapid disease progression had lower levels of anti-p24 than did infants whose disease did not rapidly progress, but not independently of HIV-1 RNA levels.

Because passively administered antibodies prevent motherto-infant transmission of other viruses, prophylactic use of human immunodeficiency virus (HIV) hyperimmune globulin is under evaluation. Studies of the association of maternal antiReceived 27 January 2000; revised 22 June 2000; electronically published 8 September 2000. Presented in part: Fourth Conference on Retroviruses and Opportunistic Infections, Washington, DC, January 1997 (abstract 505). Informed consent was obtained from patients or their guardians. Human experimentation guidelines of the US Department of Health and Human Services and those of the authors’ institutions were followed in the conduct of clinical research. Financial support: National Institute of Allergy and Infectious Disease/ National Institute of Child Health and Human Development/National Institute on Drug Abuse/National Institutes of Health (U01 AI 34858, U01 AI 34856, U01 AI 34842, U01 AI 34841, U01 AI 34840, N01 AI 35161, HD 8-2913, and R01 HD-25714). a Present affiliations: VITEX, Mellville, New York (D.H.); University of Florida, Pediatrics, Gainesville (J.L.); Lincoln Hospital, Pediatrics, Bronx, New York (H.M.). Reprints or correspondence: Dr. Jane Pitt, Columbia University College of Physicians and Surgeons, Dept. of Pediatrics, Division of Infectious Diseases, 622 W. 168th St., PH W 4-463, New York, NY 10032 (jp25@ columbia.edu). The Journal of Infectious Diseases 2000; 182:1243–6 q 2000 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2000/18204-0033$02.00

HIV antibodies with maternal HIV transmission, however, have led to conflicting results [1–5], perhaps because these studies did not control for maternal percentage of CD4 cells, virus load, duration of ruptured membranes, and maternal hard drug use, all of which are potential covariates. The association of anti-HIV antibody levels and disease progression is more consistent. Reports in both children [6] and adults [7–9] have described an independent association of low HIV-1 anti-p24 antibody with disease progression. We measured the HIV-1–specific antibodies (gp120, p66, gp41, p31, p24, and p17) of 242 HIV-infected pregnant women at delivery and of 238 of their infants enrolled in the Women and Infants Transmission Study (WITS), to evaluate their association with mother-to-infant HIV-1 transmission in the context of known predictors of transmission. The association of the decay and new synthesis of antibodies in HIV-1–exposed infants with infant infection, timing of first positive culture in infected infants, and rapid disease progression also were examined.

Methods A total of 444 mother-infant pairs were enrolled in the WITS before January 1993; maternal serum samples were available for

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Jane Pitt,1 Denis Henrard,3,a Gordon FitzGerald,5 Lynne Mofenson,7 Judy Lew,7,a George Hillyer,8 Hermann Mendez,2,a Ellen Cooper,6 Celine Hanson,9 and Kenneth C. Rich4 for the Women and Infants Transmission Study (WITS)

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Table 1. Human immunodeficiency virus type 1 mother-to-infant transmission rate, by maternal quartile antibody level at delivery (n p 242). Transmission rate in designated quartile, % (range) of CD4 in each quartile Subset Anti-gp120 Anti-p66 Anti-gp41 Anti-p31 Anti-p24 Anti-p17 a

Quartile 1 28 25 15 25 33 30

(0–11.6) (0–3.8) (0–19.7) (0–3.9) (0–4.1) (0.06–1.8)

Quartile 2 25 16 22 3 21 20

(11.6–18.3) (3.8-7.1) (19.7–21.9) (3.9–5.6) (4.1–7.0) (1.8–4.5)

Quartile 3 17 15 18 28 13 18

(18.3–22.8) (7.1–8.5) (21.9–24.5) (5.6–6.6) (7.0–8.5) (4.5–5.8)

Quartile 4 15 28 30 28 16 16

(22.8–30.4) (8.5–11.4) (24.5–28.7) (6.6–9.2) (8.5–10.0) (5.8–7.4)

a

P

.04 .75 .08 .15 .01 .07

x2 test for linear trend.

infant with antibody measurements available at consecutive visits, rates of antibody increase were compared among infected and uninfected infants with Fisher’s exact test. The overall difference between median antibody titers for infants with rapid and nonrapid progression between birth and age 6 months for individual antibodies was assessed with mixed models, with adjustment for repeated measurements over time and allowing nonlinear change in antibody over time. Assumptions of linear change over time yielded similar results.

Results Maternal HIV antibodies. The maternal analysis cohort differed from the overall WITS cohort only by being 1.4 years older, on average, and including fewer Hispanic patients and more hard drug users. Antibody levels did not significantly differ in Hispanic patients or drug users or by age, compared with the rest of the cohort. The analysis cohort’s mean maternal age was 27.9 years; 47% were black, 28% were Hispanic, 22% were white, and 3% were of other ethnic groups. Mean maternal antenatal CD3/CD4 cell percentages and absolute number were 28.4% and 537, and CD3/CD8 cell percentages and absolute number were 49.6% and 900. Of these mothers, 75% had positive HIV culture at delivery and 59% had consistently positive antenatal HIV cultures; geometric mean plasma HIV RNA at delivery was 10,439 copies/mL; 49% had ! 4 h rupture of membranes before delivery; and 59% used hard drugs and 17% used zidovudine during pregnancy. The transmission rate was 21.1% in this cohort enrolled during 1989–1993. Delivery plasmas were available for 220 mothers. Third-trimester plasma was used for the remaining 22. Mean maternal HIV antibody titers at delivery were 21.8 units for anti-gp41, 17.1 for anti-gp120, 6.1 for anti-p66, 6.1 for anti-p24, 5.1 for anti-p31, and 4.0 for anti-p17. Antibody quartile ranges are shown in table 1. There was a negative correlation between CD4 lymphocyte percentages at delivery and anti-gp41 levels (P p .004) and a positive correlation between CD4 lymphocyte percentages and anti-p17 (P p .02). Higher maternal anti-p24 and anti-gp120 antibodies were associated with lower vertical transmission rates (table 1), but no threshold levels for antibody-associated transmission risk were apparent. Low maternal anti-gp41 and high maternal anti-p17 levels

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286 women and 280 infants. Patient samples from repeat pregnancies and from infants with indeterminate HIV infection status were excluded, leaving samples from 242 mothers and 238 infants available for analysis. HIV antibody titers were assessed on stored maternal plasma samples obtained at delivery or, if no delivery sample was available, a sample from the third trimester. Infant antibodies were assessed on stored infant plasma samples obtained at birth and at 1, 2, 4, and 6 months after birth. Antibody levels to 6 major proteins of HIV-1 (gp120, p66, gp41, p31, p24, and p17) were measured in a blinded fashion by use of an automated dot blot assay with purified recombinant antigens from HIV-1 III-B (for antibodies to p66, gp41, p31, p24, and p17) and HIV SF2 gp120 peptide with the MATRIX analyzer (Abbott Laboratories, North Chicago, IL) according to methods described elsewhere [8]. HIV-specific reactivity was expressed as the reciprocal of the natural log of reflectance divided by cutoff of assay [9]. Definitions of infant infection status have been described elsewhere [10, 11]. Infected infants who progressed to AIDS-related death or HIV-related death by age 18 months were considered to be rapid progressors. Infected infants whose first positive culture was at age ! 48 h were considered to have early infection, whereas those with >1 negative culture and no positive cultures in the first week of life were considered to have late infection. Maternal HIV virus load during pregnancy was determined in AIDS Clinical Trials Group (ACTG)–certified laboratories and was analyzed as always/not always culture positive, as mean peripheral blood mononuclear cells infectious units per million [12], and as mean antenatal RNA copy number per milliliter. HIV RNA was measured with the Roche Amplicor HIV monitor kit (Roche Molecular Systems, Somerville, NJ). Immune complex dissociated (ICD) p24 levels were determined with the Dupont ICD p24 antigen assay (NEN, Boston). Immunophenotyping was performed in ACTG-certified laboratories with standardized lots of monoclonal antibodies (Becton Dickinson, San Jose, CA). Maternal vitamin A levels at all pregnancy visits through 24 h after delivery were measured in a single laboratory by high-performance liquid chromatography. Hard drug use was defined as use of heroin, cocaine, or methadone, or the use of any drug by injection. The relationship of antibody quartile with rate of transmission was examined with single degree of freedom trend tests. Logistic regressions examined the relationship between antibody levels and transmission, adjusted for mean pregnancy percentage of CD4 cells, HIV culture positivity, log HIV RNA copy number, and ICD p24 antigen level (detectable vs. not detectable). For each

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HIV-1 Antibodies and Perinatal Disease

Discussion Although we saw a significant association of maternal specific anti-HIV antibody and transmission, this association lost statistical significance when we controlled for maternal HIV RNA copy number. This may reflect the relative precision and dy-

Figure 1. Median anti–human immunodeficiency virus (HIV) type 1–specific antibodies in maternal delivery specimens and in their HIVinfected infants with rapid and nonrapid disease HIV progression from birth to age 6 months: top, anti-p17 antibody (P ! .20); center, antip24 antibody (P ! .01); bottom, anti-gp120 antibody (P p .17).

namic range of the 2 assays. However, anti-HIV antibody and HIV RNA levels are strongly correlated, making it difficult to determine the relative roles of antibody and virus load in transmission. High levels of antibody could actively neutralize virus, lowering virus load and, thus, transmission risk. On the other hand, high virus load, which increases the risk of transmission, could result in complexing, thus lowering detectable antibody levels. Anti-gp41 and anti-gp120 antibody titers declined to a greater extent in infected infants than in uninfected infants during the first 2 months of life. It has been shown that perinatally infected neonates have very high HIV RNA levels as early as age 1 month [11]. Thus, the rapid decline in anti–HIV envelope antibodies may reflect complexing of the virus by antibody in the infected infants, with subsequent antibody-antigen complex clearance. Infected infants also demonstrated new antibody synthesis as early as age 1–2 months to p17 and p24 antigens, which may have also obscured the decline in transplacentally acquired maternal antibodies to these antigens. Schupbach et al. [13] examined the specific antibody bands in Western blot tests and, as in this study, noted the appearance of both envelope- and

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were marginally associated with lower transmission rates, whereas there was no association of transmission with antibodies to p66 and p31, both nonstructural proteins. Associations persisted when we controlled for infant gestational age, maternal duration of ruptured membranes, maternal hard drug use, antenatal albumin levels, vitamin A levels, and CD4 lymphocyte percentages, but became nonsignificant when controlled for HIV RNA copy number, whereas HIV RNA remained significantly associated with transmission when adjusted for anti-HIV antibody. The odds ratios for both, however, became closer to 1, and the P values became less significant than in the unadjusted models. For anti-p24, the unadjusted and adjusted odds ratios were 0.85 (P p .002) and 0.89 (P p .074), whereas for HIV RNA, these values were 1.75 (P p .015) and 1.57 (P p .045). Maternal anti-HIV antibodies were not associated with early or late culture positivity or with rapid disease progression in infants. Pediatric HIV antibodies. A total of 710 samples were available from 238 infants, 55 of whom were infected and 183 of whom were uninfected. A significant positive correlation between maternal delivery antibody levels and infant birth antibody levels was found for both transmitting and nontransmitting pairs. The Spearman correlation coefficients are .79–.95 for individual antibody comparisons (P ! .0001 ). Differences in the pattern of antibody titer changes between infected and uninfected infants after delivery were detected. From ages 1–2 months, anti-gp120, anti-gp41, anti-p31, and anti-p66 decayed to a greater extent in infected than in uninfected infants. An increase in anti-p24 antibody titer was observed more frequently in infected than in uninfected infants as early as age 1–2 months (9 of 21 infected infants, compared with 12 of 65 uninfected infants, had an increase in p24 antibody titer; P p 0.04). An increase in p17 antibody titer was more frequent in infected infants starting at age 2–4 months (P ! .001) and for anti-gp41 and anti-gp120, starting at age 4–6 months (P ! .001 and P p .07, respectively). Infected infants with rapid HIV disease progression had significantly lower anti-p24 antibody titers during the first 6 months of life than did nonrapid progressors (figure 1; P ! .01). Titers to anti-p17 or anti-gp120 antibodies, although following the same trend (figure 1, P p .20 and .17, respectively), were not statistically significantly associated with disease progression, nor were anti-p41, anti-p31, or anti-p66 antibody titers (data not shown). The association of rapid progression with anti-p24 antibody titers was independent of CD4 lymphocyte percentage at the corresponding visit, but not of HIV RNA copy number (data not shown).

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Acknowledgments Principal Investigators, study coordinators, and program officers for the Women and Infants Transmission Study include the following: Clemente Diaz and Edna Pacheco-Acosta (University of Puerto Rico, San Juan); Ruth Tuomala, Ellen Cooper, and Donna Mesthene (Boston/ Worchester Site, Boston); Jane Pitt and Alice Higgins (Columbia Presbyterian Hospital, New York); Sheldon Landesman, Hermann Mendez, and Gail Moroso (State University of New York, Brooklyn); Kenneth Rich and Delmyra Turpkin (University of Illinois at Chicago); William Shearer, Celine Hanson, and Norma Cooper (Baylor College of Medicine, Houston); Mary Glenn Fowler, Judy Lew, and Elaine Matzen (National Institute of Allergy and Infectious Disease, Bethesda, MD);

Anne Willoughby, David Burns, Jack Moye, Jennifer Read, and Lynne Mofenson (National Institute of Child Health and Human Development, Bethesda, MD); Vincent Smeriglio (National Institute on Drug Abuse, Rockville, MD); and Sonja McKinley, Les Kalish, and Susan Ellis (New England Research Institutes, Watertown, MA). References 1. Jackson JB, Kataaha P, Hom DL, et al. b2-Microglobulin, HIV-1 p24 antibody and acid-dissociated HIV-1 p24 antigen levels: predictive markers for vertical transmission of HIV-1 in pregnant Ugandan women. AIDS 1993; 7:1475–9. 2. Husson RN, Lan Y, Kojima E, Venzon D, Mitsuya H, McIntosh K. Vertical transmission of human immunodeficiency virus type 1: autologous neutralizing antibody, virus load, and virus phenotype. J Pediatr 1995; 126: 865–71. 3. St. Louis ME, Pau C-P, Nsuami M, et al. Lack of association between AntiV3 loop antibody and perinatal HIV-1 transmission in Kinshasa, Zaire, despite use of assays based on local HIV-1 strains. J Acquir Immune Defic Syndr 1994; 7:63–7. 4. Scarlatti G, Leitner T, Halapi E, et al. Comparison of variable region 3 sequences of human immunodeficiency virus type 1 from infected children with the RNA and DNA sequences of the virus populations of their mothers. Proc Natl Acad Sci U S A 1993; 90:1721–5. 5. Khouri YF, McIntosh K, Cavancini L, et al. Vertical transmission of HIV1 correlation with maternal viral load and plasma levels of CD4 binding site anti-gp120 antibodies. J Clin Invest 1995; 95:732–7. 6. Mofenson L, Harris R, Rich K, Meyer W, et al. Serum HIV-1 antibody, HIV1 RNA copy number and CD4 lymphocyte percentage are independently associated with risk of mortality in HIV-1 infected children. AIDS 1999;13: 31–9. 7. Allain J-P, Laurian Y, Einstein MH, et al. Monitoring of specific antibodies to human immunodeficiency virus structural proteins: clinical significance. Blood 1991; 77:1118–23. 8. Farzadegan H, Henrard DR, Kleeberger CA, et al. Virologic and serologic markers of rapid progression to AIDS after HIV-1 seroconversion. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13:448–55. 9. Allain JP, Laurian Y, Paul DA, et al. Long-term evaluation of HIV antigen and antibodies to p24 and gp41 in patients with hemophilia: potential clinical importance. N Engl J Med 1987; 317:1114–21. 10. McIntosh K, Pitt J, Brambilla D, et al. Blood culture in the first six months of life for the diagnosis of vertically transmitted human immunodeficiency virus infection. J Infect Dis 1994; 170:996–1000. 11. Shearer W, Quinn T, LaRussa P, et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. N Engl J Med 1997; 336:1337–42. 12. Dimitrov DH, Melnick JL, Hollinger FB. Microculture assay for isolation of human immunodeficiency virus type 1 and for titration of infected peripheral blood mononuclear cells. J Clin Microbiol 1990; 28:734–7. 13. Schupbach J, Tomasik Z, Jendis J, Boni J, Seger R, Kind C. IgG, IgM and IgA response to HIV in infants born to HIV-1 infected mothers. J Acquir Immune Defic Syndr 1994; 7:421–7. 14. Henrard D, Fauvel M, Samson J, et al. Ontogeny of the humoral immune response to human immunodeficiency virus type 1 in infants. J Infect Dis 1993; 168:288–91. 15. Binley JM, Klasse PJ, Cao Y, et al. Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. J Virol 1997; 71:2799–809.

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gag-reactive antibodies as early as 1–3 months in infected infants; they also found more rapid decay of envelope antibodies in infected than in uninfected infants. The possible association of anti-p24 antibody titers with HIV disease progression in infected infants is consistent with recent reports in HIV-infected children. Henrard et al. [14] reported that 4 HIV-infected infants who were symptomatic at age 1 year failed to make any HIV-specific antibodies, whereas 8 asymptomatic infants were producing >1 HIV antibodies at a median age of 6 months. Mofenson and colleagues [6] reported that the risk of long-term mortality was found to be independently associated with anti-p24 antibody, CD4 lymphocyte percentage, and HIV-1 RNA copy number in a multivariate analysis of an older cohort of HIV-infected children. In the current report, the association of infant antiHIV antibody levels and HIV disease progression was not found to be independent of infant plasma HIV-1 RNA copy number. However, the association of low anti-p24 antibody titers with disease progression in adults is not thought to be simply due to complexing of antibody with HIV in patients with high virus load or virus neutralization [6]. It has been suggested that T cell helper function is more essential for production of antibodies to p24 core than to glycosylated gp120 envelope antigens [15]. Thus, low anti-p24 antibody in older children with rapidly progressing disease may not be simply a marker of high virus load but a marker of progressive CD4 T helper cell dysfunction. In summary, the association of certain anti-HIV antibodies with perinatal transmission and with HIV disease progression in infected infants was not independent of HIV-1 RNA levels, but the 2 were very highly correlated. If larger studies support the independent association of these antibodies with transmission or disease progression in young infants, as found in older children, further investigation must determine whether they are surrogates for immunologic function, virus load, or both, or whether they have an intrinsically protective role.

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