Publications

OBJECTIVE

Persistent systemic inflammation is associated with the inability of some HIV-infected patients to normalize circulating CD4 T-cell levels after years of suppressive antiretroviral therapy. In this study, we sought to understand whether such systemic inflammation is also associated with detectable signs of inflammation in biopsies from the rectosigmoid colon.

DESIGN

Immunologic and virological parameters were studied in the peripheral blood and in rectosigmoid colon biopsies from individuals with viral suppression for at least 2 years and with peripheral CD4 T-cell levels of <350 cells per cubic millimeter (immunologic nonresponders, n = 18) or >500 cells per cubic millimeter (immunologic responders, n = 16).

METHODS

Peripheral blood and rectosigmoid colon biopsies were analyzed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction.

RESULTS

Nonresponders had elevated T-cell activation and inflammatory cytokines in the circulation, but inflammatory gene expression in colon biopsies was not different as compared with responders, and there was little relationship between blood and colon markers of inflammation. Blood inflammatory markers were positively associated with soluble CD14 levels indicative of monocyte activation.

CONCLUSIONS

These findings demonstrate that, in the context of treated HIV disease, it is easier to detect parameters of inflammation (including blood monocyte activation) in the peripheral blood than in isolated rectosigmoid colon biopsies. Accordingly, interventions to block such inflammation in this population might be most conveniently and accurately assessed in blood.

We compared different techniques for measuring gut HIV reservoirs and assessed for HIV in non-CD4 T cells. HIV DNA levels were similar when measured from rectal biopsies and isolated rectal cells, while HIV RNA tended to be higher in rectal cells. HIV DNA levels in total rectal cells were greater than those predicted from levels in sorted CD4 T cells, suggesting a reservoir in non-CD4 T cells, and HIV DNA was detected in sorted myeloid cells (7/7 subjects).

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.

OBJECTIVE

HIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs).

METHODS

ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models.

RESULTS

After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63√CD4/month), followed by +0.19√CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048).

CONCLUSIONS

cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.

OBJECTIVES

Suppressive antiretroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda.

DESIGN

Observational cohort study.

METHODS

We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was more than 400 copies/ml and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with at least 1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days.

RESULTS

We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However, only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4 cell count, low household asset ownership and increased internalized stigma.

CONCLUSION

Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to 6 years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.