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Monitoring the CD4/CD8 ratio: a promising indicator of disease progression in HIV-infected individuals?
Sergio Serrano-Villar*,1, Talía Sainz2 & Santiago Moreno1 Over the last three decades, CD4 count monitoring has guided the clinical management of HIV infection. These cell numbers have been used in the clinic to direct diagnostic workups, to decide prophylaxis for opportunistic infections, and to determine initiation of antiretroviral therapy (ART). However, the usefulness of CD4 monitoring has recently raised a vivid debate. It has been shown that in stable patients who achieve complete virological suppression and immunological recovery under ART, CD4 counts exceptionally drop below clinically meaningful thresholds [1] . So, in this situation monitoring CD4 counts very rarely influences care. Indeed, the most recent version of Department of Health and Human Services guidelines acknowledges that in stable patients with an adequate immunovirological response to ART, the CD4 cell count provides limited information. Accordingly, this panel of experts
advocates reducing the frequency of CD4 monitoring [2] . However, while many HIV specialists are reluctant to reduce CD4 monitoring, probably as a consequence of more than 30 years of ‘CD4 culture’ for both HIV specialists and patients, some experts are encouraging to stop CD4 monitoring in all suppressed patients. The rationale is that, even among those patients with incomplete immunological response, CD4 monitoring is meaningless, as no ART regimen or immune-based strategy has shown a clinically relevant positive result [3,4] . Moreover, since the beginning of the HIV epidemic, the clinical focus has dramatically shifted from treatment of opportunistic infections, to follow-up of stable patients and screening and prevention of age-related conditions. A higher than expected risk of non-AIDS complications, including cardiovascular disease and cancer, has consistently been demonstrated
KEYWORDS
• CD4+ T cells • CD8+ T cells • HIV • immunosenescence • mortality
Department of Infectious Diseases, University Hospital Ramón y Cajal, Carretera de Colmenar Viejo, s/n. 28034 Madrid, Spain 2 Department of Pediatric Infectious Diseases, University Hospital La Paz, Paseo de la Castellana, 261. 28046 Madrid, Spain *Author for correspondence:
[email protected] 1
10.2217/FVL.14.85 © 2015 Future Medicine Ltd
Future Virol. (2015) 10(1), 1–4
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Editorial Serrano-Villar, Sainz & Moreno in treated individuals. Hence, in the last decade a great focus of the HIV scientific community has been the identification of biomarkers that may discriminate individuals at increased risk of non-AIDS complications. There is now an emerging consensus that persistent inflammation, independently of CD4 counts, contributes to this excess risk of morbidity and mortality [5] . In our opinion, the overwhelming importance of the CD4 and plasma HIV RNA monitoring in the clinical management of HIV-infected subjects might have led to overlook the value of an old biomarker, the CD4/CD8 ratio, which in the current clinical scenario might become a better surrogate marker of ART efficacy. CD8+ T-cell expansion & low CD4/CD8 ratio during treated HIV infection reflect underlying immune dysfunction & excess risk of non-AIDS-related mortality As observed in other viral infections, acute HIV infection results in expansion of effector CD8 + T cells, contributing to an early inversion (below 1) of the CD4/CD8 ratio. However, unlike other viral infections, expansion of the CD8 + T-cell pool is not limited only to HIV-specific reactive cells, and bystander CD8 + T-cell activation by antigen-dependent (e.g., other microorganisms such as CMV and EBV) and antigen-independent mechanisms (e.g., sustained expression of inflammatory cytokines such as IFN-α, IL-1b and IL-15) might play a role in the profound and persistent memory CD8 + T-cell expansion that characterizes HIV infection [6] . Importantly, while CD4 + T-cell recovery is an achievable goal in the majority of patients, during ART the CD8 + T-cell compartment remains expanded in many patients, resulting in lack of CD4/CD8 ratio normalization [7–10] . Mechanistically, several studies have shown a number of correlations between the CD4/CD8 ratio and different factors, which in turn have been linked to inflammation in treated infection. For example, this ratio has been associated with higher levels of inflammation and disruption of the mucosal immunity [11] , increased CMV-specific T-cell responses [12] and markers of HIV persistence [13] . These observations suggest that persistence of low CD4/CD8 ratios during ART might be fueled by the same factors that promote inflammation and immune dysfunction [5] . Importantly, the CD4/CD8 ratio inversion is a hallmark of the age-associated decline in immune function (‘immunosenescence’) and
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an independent predictor of all-cause mortality in the elderly [14] . Although some features of the HIV-associated immunosenescence in treated infection differ from that observed in the elderly [15] , both conditions share many traits. For example, treated infection and aging are characterized by telomere shortening, accumulation of dysfunctional and senescent CD28T cells, expansion of CMV-specific CD8 + T cells and an increase of inflammatory markers [16] . In different recent studies, we and others have described the phenotype of expanded CD8 + T cells driving a low CD4/CD8 ratio during treated infection [11,17–19] , showing an expansion of activated (HLA-DR+ CD38 +) and senescent (CD28-) CD8 + T cells, as well as skewing of the CD8 + T-cell repertoire from naive toward effector memory cells. These observations imply that persistence of a low CD4/CD8 ratio is associated with high levels of activation and senescence of the adaptive immunity. More importantly, different studies have provided indirect evidence that a low CD4/CD8 ratio could be a marker of age-associated complications, such as cardiovascular disease [20] or frailty [21] . In keeping with these data, we observed that among successfully treated HIV-infected individuals (>350 CD4 cells/mm3), a low CD4/CD8 ratio correlated with markers of age-associated disease (carotid intima–media thickness, arterial stiffness and lower estimated glomerular filtration rate) [22] . These observations were suggestive that a low ratio might not only reflect immunosenescence, but also higher risk of fatal nonAIDS complications. We tested this hypothesis in ART-suppressed with optimal CD4 count recovery, that is, above 500 CD4 counts. Using data from different cohorts, we showed that a low CD4/CD8 ratio identifies individuals with prominent features of immune dysfunction, and, noteworthy, these patients also exhibit higher risk of non-AIDS morbidity and mortality [11,23] . In contrast, those who normalize the CD4/CD8 ratio exhibited traits of a healthy immune system and better prognosis. Is the CD4/CD8 ratio a novel biomarker to monitor HIV infection? Since the CD4/CD8 ratio might help to further discriminate the risk of disease progression of treated HIV-infected individuals, a successful response to ART may require both normalization of the CD4 count and the ratio of CD4 + to CD8 + T cells. We believe that, in the current
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Monitoring the CD4/CD8 ratio clinical scenario where most patients will be able to maintain long-life viral suppression, the CD4/CD8 ratio might prove more useful than the CD4 counts. Early in the epidemic, it was observed that the CD4/CD8 ratio provides similar ability to predict AIDS than the CD4 counts or the CD4 percentage [24] . In addition, in successfully treated patients the ratio retains the prognostic information driven by a low CD4 count (and presumably immunodeficiency), but also reflects the harm associated with CD8 + T-cell expansion (and presumably inflammation), and predicts non-AIDS-related mortality independently of CD4 counts and CD4 nadir [11,23] . This association between the CD4/CD8 ratio and non-AIDS-related mortality is independent of the CD4 count and has been reproduced in the large Italian ICONA cohort [10] . Hence, a low CD4/CD8 ratio identifies a subset of individuals, apparently doing well on ART but at higher risk of disease progression. From our perspective, the CD4/CD8 ratio monitoring could be used in the clinic to identify individuals in need of more intensive screening of non-AIDS complications or aggressive management of concomitant risk factors for age-associated diseases, such as smoking, diabetes or dyslipidemia. In addition, these subjects might also be ideal candidates for trials with novel therapies aimed at reducing residual immune dysfunction and inflammation. Given previous studies reporting a negative correlation between the CD4/CD8 ratio and markers of HIV persistence subjects [13,25] , patients with a high CD4/CD8 ratio may be useful candidates for HIV eradication trials. Although inversion of the CD4/CD8 ratio (i.e., =300 cells/μl and HIV-1 suppression? Clin. Infect. Dis. 56(9), 1340–1343 (2013). Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov Havlir DV. Adieu CD4 monitoring?. http://hivinsite.ucsf.edu
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immunosenescence that predicts mortality in the elderly [14] , a lower cutoff (
