CD4+ and CD8+ T Cell Activation Are Associated with HIV DNA in Resting CD4+ T Cells

Cockerham, Leslie R.; Siliciano, Janet D.; Sinclair, Elizabeth; O’Doherty, Una; Palmer, Sarah; Yukl, Steven A.; Strain, Matt C.; Chomont, Nicolas; Hecht, Frederick M.; Siliciano, Robert F.; Richman, Douglas D.; Deeks, Steven G.

doi:10.1371/journal.pone.0110731

Cited by 97 publications

(80 citation statements)

References 39 publications

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“…In any case, we observed changes in the correlations between viral reservoir measurements and HIV-1-specific T cell immune responses before and after vaccinations in both DC-HIV-1 and DC-control groups. No correlations were observed before vaccination, in accordance with the data of other authors who have not found significant associations between the viral reservoir and HIV-specific CD8 T cell counts (19,25). Conversely, a significant inverse correlation was observed after vaccination (and before cART interruption) in vaccinated patients, and a direct correlation was observed in controls.…”

Section: Discussionsupporting

confidence: 90%

“…Third, although we did not find any association between immune activation/dysfunction and total or integrated HIV-1 DNA levels during vaccination, those patients with higher senescence levels or memory CD4 T cell counts after vaccination had significantly higher levels of integrated HIV-1 DNA after cART interruption. The association between immune activation and/or dysfunction and total HIV-1 DNA levels during effective cART has been extensively analyzed, and while some studies reported a significant association (25), others failed to confirm these findings (20,28,29). Conversely, few studies have addressed the correlation between senescence and/or activation and viral reservoir replenishment.…”

Section: Discussionmentioning

confidence: 99%

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HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

Andrés

Plana

Guardo

et al. 2015

J Virol

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HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n ‫؍‬ 24) (DC-HIV-1) or nonpulsed DCs (n ‫؍‬ 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log 10 to 1.9 copies/10 6 CD4 T cells, P ‫؍‬ 0.22) and did increase in controls (mean of 1.8 log 10 to 2.1 copies/10 6 CD4 T cells, P ‫؍‬ 0.02) (P ‫؍‬ 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] ‫؍‬ ؊0.69, P ‫؍‬ 0.002, and r ‫؍‬ ؊0.82, P < 0. 0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.) IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

Andrés

Plana

Guardo

et al. 2015

J Virol

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“…In untreated patients with abundant unintegrated HIV DNA, total HIV DNA loads in blood cells correlate strongly with the level of CD8 and CD4 T cell activation (187). In antiretroviral-treated adults, total HIV DNA in resting CD4 T cells is strongly associated with CD4 and CD8 T cell activation, whereas there is no association between cell activation and integrated DNA or IUPM coculture results (254). Cell-associated HIV RNA load, which reflects the level of viral transcription, including abortive transcription, also correlates with immune activation in untreated patients, patients on cART, and natural controllers (204,255,256,257).…”

Section: Discussionmentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…As a tool to measure the frequency of activated T lymphocytes, we chose the widely validated activation marker HLA-DR (27). We found that the macaques that had received ART, auranofin, and BSO displayed a lower frequency of HLA-DR ϩ T lymphocytes at viral rebound (Fig.…”

Section: Auranofin and Bso Kill Activated T Lymphocytes In Vitromentioning

confidence: 99%

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

Shytaj

Nickel

Arts

et al. 2015

J Virol

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Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4؉ T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir. IMPORTANCE The HIV reservoir in CD4؉ T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4 ؉ T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.

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CD4+ and CD8+ T Cell Activation Are Associated with HIV DNA in Resting CD4+ T Cells

Cited by 97 publications

References 39 publications

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

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