Prevalence and T-cell phenotype of slow HIV disease progressors with robust HIV replication.

To the Editor: Some HIV-infected individuals appear to maintain stable CD4 counts despite high viral replication. Considering that plasma HIV RNA level explains only a small part of the variability of CD4 decline, differences in host-mediated immune responses to viral antigen may be an important factor in determining the pace of HIV-1 disease progression. We hypothesized that some HIV-1infected individuals better tolerate high viral replication and respond with less immune activation resulting in improved CD4 T-cell maintenance during untreated HIV-1 infection. To evaluate this, we conducted a cross-sectional study within a university-based HIVoutpatient clinic to determine the prevalence of slow HIV disease progressors with robust viral replication and determine if these individuals have a lower proportion of T-lymphocytes expressing markers of immune activation within differentiation stages, proliferation, activation-induced apoptosis and greater expression of regulatory function and na€ıve phenotype markers than fast progressors. Eligible HIV-1-infected subjects were asymptomatic and antiretroviralna€ıve with at least 6 months of follow up, three or more CD4 measurements, and a mean viral load above 20,000 copies/mL. The slope of CD4T-cell decline was calculated by least squares linear regression method of all available CD4 measurements. Subjects were then qualitatively categorized as ‘‘fast progressors’’ if CD4 decline was consistent with rates observed in other untreated cohorts or, if less, as ‘‘slow progressors. ’’ Slow progressors were randomly selected among eligible patients from the Owen HIV Outpatient Care Center and compared with a convenience sample of recently HIV-diagnosed, asymptomatic individuals with declining CD4 counts (ie, fast progressors) who met the same selection criteria. After appropriate written and informed consent was obtained from all study participants, demographic/ laboratory data and blood samples for peripheral blood mononuclear cells (PBMCs) were collected. No clinical/ laboratory data were collected or analyzed for subjects identified as slow progressors but for whom consent was not obtained and/or were not contacted. Finally, stored PBMC samples from 10 HIV uninfected individuals were evaluated as a second comparator group. Statistical tests were performed using the open source statistical package R (Version 1.7.0). Records of all new patients from January 2000 to July 2006 were evaluated (n = 2793). Subjects were excluded if they were treatment-experienced (n = 1670), lost to follow up (n = 570), had a history of an AIDS-defining illness (n = 197), or had insufficient laboratory data (n = 86). Of the 467 newly presenting, antiretroviral-na€ıve patients, we identified 19 as slow progressors (4.1% period prevalence). Of these 19 slow progressors, PBMC samples in six were compared with samples obtained from six fast progressors. Both slow progressors and fast progressors had high presenting CD4 counts (648 versus 572 cells/mL, respectively) and similar durations of HIV infection (3 versus 2.5 years, respectively). Medianannual ratesofCD4declineamong slow progressors were –5.6 cells/mm per year versus –84.3 cells/mm per year despite similar viral loads (4.59 log10 [39,743] copies/mL versus 4.82 log10 [67,075] copies/mL; P > 0.3). Because variability in CD4 measurement can increase at higher counts, individual rates of CD4 decline were also adjusted by presenting CD4 counts. Overall, slow progressors lost less than 1% of their initial CD4 count per year, whereas progressors lost 18% per year. To determine if increased immune activation, proliferation, and apoptosis were associated with more rapid CD4 decline, we determined the frequency of these subsets between slow and fast progressors and compared them with HIV-1-uninfected controls. Immune activation was defined as the proportion of CD4 and CD8 T-cells expressing CD38 with or without HLA-DR coexpression and was measured in various maturation phenotypes, including early (CD45RACD27), intermediate (CD45RA CD27 ), and late (CD45RACD27 ) differentiation steps (Table 1). HIV-1-uninfected controls displayed less immune activation within these CD4 and CD8 T-cell subsets (all P < 0.01); however, no difference was observed between slow and fast progressors. Similarly, CD4 and CD8 T-cell proliferation (Ki67) was also significantly less in HIV-1-uninfected controls but did not differentiate slow and fast progressors. Although the proportion of PHA-stimulated CD4 and CD8 (Annexin V) were similar among all three groups, unstimulated (CD69Annexin V) CD4 and CD8 T-cells undergoing apoptosis were significantly lower in HIV-uninfected controls but, again, did not differentiate rates of disease progression. In this study, we did not evaluate markers of thymic output or peripheral expansion to determine whether increased CD4 production explains the difference in slow versus fast disease progression. Rather, we evaluated the proportion of na€ıve T-cells and regulatory CD4 T-cell (Table 1) because depletion of regulatory T-cells has been associated with increased immune activation and lower CD4 T-cell counts during untreated HIV-1 infection. The proportion of na€ıve (CDRACD27) CD4 T-cells was similar for HIV-1uninfected and HIV-infected with slow and fast disease progression (median, 38%, 44%, and 50%, respectively). Frequencies of na€ıve CD8 T-cells were also similar between HIV-1-uninfected Thisworkwas supportedbygrants from theNational Institute ofAllergyand InfectiousDiseases (K23 AI066901), the California HIV/AIDS Research Program (CH05-SD-607-005), and the Department of Veterans Affairs (MR award to C.S.). Research support was also provided through the General Clinical Research Center of UCSD (5M01 RR000827) and the Clinical and Flow Cytometry Research Core Facility of the San Diego Center for AIDS Research (5P30 AI 36214), the Veterans Medical Research Foundation and the VA San Diego Healthcare System.