Clonal expansion of infected CD4⁺ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4⁺ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone’s response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.

Context: Immunological similarities have been noted between HIV-infected individuals and older HIV-negative adults. Immunologic alterations with aging have been noted in frailty in older adults, a clinical syndrome of high risk for mortality and other adverse outcomes. Using a frailty-related phenotype (FRP), we investigated in the Multicenter AIDS Cohort Study whether progressive deterioration of the immune system among HIV-positive individuals independently predicts onset of FRP. Methods: FRP was evaluated semiannually in 1046 HIV-infected men from 1994 to 2005. CD4 T-cell count and plasma viral load were evaluated as predictors of FRP by logistic regression (generalized estimating equations), adjusting for age, ethnicity, educational level, AIDS status, and treatment era [pre-highly active antiretroviral therapy (HAART) (1994-1995) and HAART (1996-1999 and 2000-2005)]. Results: Adjusted prevalences of FRP remained low for CD4 T-cell counts >400 cells per cubic millimeter and increased exponentially and significantly for lower counts. Results were unaffected by treatment era. After 1996, CD4 T-cell count, but not plasma viral load, was independently associated with FRP. Conclusions: CD4 T-cell count predicted the development of a FRP among HIV-infected men, independent of HAART use. This suggests that compromise of the immune system in HIV-infected individuals contributes to the systemic physiologic dysfunction of frailty.

We examined the emergence of CXCR4 (i.e., X4) tropism in 67 male human immunodeficiency virus type 1 (HIV-1) seroconverters from the Multicenter AIDS

Background: Men who have sex with men (MSM) have been disproportionately affected by HIV-1 since the beginning of the AIDS pandemic, particularly in the USA and Europe. Compared to men who have sex with women (MSW), MSM have a distinct fecal microbiome regardless of HIV-1 infection. However, it is unclear whether the MSM-associated gut microbiome affects the susceptibility and progression of HIV-1 infection. We studied fecal microbiome profiles, short-chain fatty acids, and blood plasma inflammatory cytokines of 109 HIV-1 seroconverters (SC) from the early, 1984–1985 phase of the HIV-1 pandemic in the Multicenter AIDS Cohort Study (MACS) before and after HIV-1 infection compared to 156 HIV-1-negative MACS MSM (negative controls [NC]). Results: We found that family Succinivibrionaceae, S24-7, Mogibacteriaceae, Coriobacteriaceae, and Erysipelotrichaceae were significantly higher (p<0.05), whereas Odoribacteraceae, Verucomicrobiaceae, Bacteroidaceae, Barnesiellaceae, and Rikenellaceae were significantly lower (p<0.05), in SC before HIV-1 infection compared to NC. At the species level, Prevotella stercorea, Eubacterium biforme, and Collinsella aerofaciens were significantly higher (p<0.05), and Eubacterium dolichum, Desulfovibrio D168, Alistipes onderdonkii, Ruminococcus torques, Bacteroides fragilis, Bacteroides caccae, Alistipes putredinis, Akkermansia muciniphila, Bacteroides uniformis, and Bacteroides ovatus were significantly lower (p<0.05) in SC before HIV-1 infection compared to NC. After HIV-1 infection, family Prevotellaceae and Victivallaceae and species Bacteroides fragilis and Eubacterium cylindroides were significantly higher (p<0.05) in SC who developed AIDS within 5 years compared to the SC who were AIDS free for more than 10 years without antiretroviral therapy (ART). In addition, family Victivallaceae and species Prevotella stercorea, Coprococcus eutactus, and Butyrivibrio crossotus were significantly higher (p<0.05) and Gemmiger formicilis and Blautia obeum were significantly lower (p<0.05) after HIV-1 infection in SC who developed AIDS within 5–10 years compared to the SC who were AIDS-free for more than 10 years without ART. Furthermore, plasma inflammatory cytokine levels of sCD14, sCD163, interleukin 6, and lipopolysaccharide binding protein were significantly higher in SC with p<0.05 before HIV-1 infection compared to NC. Conclusions: Our results suggest that pathogenic changes in the gut microbiome were present in MSM several months prior to infection with HIV-1 in the early phase of the AIDS pandemic in the USA. This was associated with increased inflammatory biomarkers in the blood and risk for development of AIDS.

HIV-1 infection is characterized by an inverted CD4/CD8 T-cell ratio, but the distribution of inversions over time after seroconversion and whether delay of inversion is associated with a favorable prognosis are not known. T-cell counts and clinical outcomes among men in the Multicenter AIDS Cohort Study who had incident HIV-1 infection before December 31, 1995 were analyzed by Kaplan-Meier and Cox proportional hazards methods. Results were also analyzed by time-dependent multivariate methods to adjust for CD4 lymphocyte counts, viral loads, age, race, and polymorphisms in host chemokine receptor genes (CCR5-Δ32 and CCR2-64I). Among 424 cases whose date of seroconversion was known to within ±4.5 months, 317, 52, and 55 inverted their CD4/CD8 ratio within less than 1, 1 to 2, and more than 2 years of seroconversion, respectively. Longer time to inversion was significantly associated with longer time to AIDS, even after adjusting for CD4 lymphocyte count and viral load at the first seropositive visit and over the first 3 seropositive visits. Of the 6 seroconverters who had more than 500 CD4 lymphocytes 10 years after seroconversion without receiving highly active antiretroviral therapy, 5 took more than 2 years to invert their CD4/CD8 ratio. Time from HIV-1 seroconversion to inversion of the CD4/CD8 ratio independently predicted time to AIDS. Early measurements of the CD4/CD8 ratio until inversion occurs may identify people likely to become long-term nonprogressors or slow progressors, thus facilitating detailed studies of the mechanism of HIV-1 disease progression.

Background: Frailty is associated with immune activation and inflammation in the elderly general population, but whether this is true in the younger HIV-infected (HIV+) population is not known.Methods: We analyzed 24 serologic biomarkers of monocyte, T-cell, or B-cell activation in HIV− (n = 207) and HIV+ (n = 714; 75% virologically suppressed) men who have sex with men in the Multicenter AIDS Cohort Study (MACS) and were classified as frail or nonfrail according to expression or nonexpression of the frailty phenotype at 2 consecutive study visits.Results: After correction for multiple comparisons and adjustment for age, race, study site, and education, frailty in HIV+ men was significantly (P< 0.002) associated with higher levels of sCD14, sIL2Rα, sTNF-R2, IL-6, and TNF-α; the association with higher levels of C-reactive protein (CRP) approached significance (P= 0.003). After further adjustment for body mass index (BMI), smoking, and comorbidities, only the association with C-reactive protein was significant atP< 0.002, with levels approximately 50% higher in frail compared with nonfrail men. These conclusions were not altered by restricting the analysis to HIV+ men who were virologically suppressed. Among HIV− men, none of these markers differed significantly by frailty.Conclusions: These data suggest that frailty in virologically suppressed HIV+ men was associated with immune activation beyond that due to treated HIV infection. The inflammatory markers associated with frailty were primarily products of activated monocytes/macrophages. Much, but not all, activation was accounted for by harmful behaviors and comorbidities. However, C-reactive protein, which is regulated by IL-6, was elevated in HIV+ frail men independent of these factors.