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

Abstract

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.

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

“…Following suspension of ART, the virus was apparently eradicated (119). That induction of oxidative or nitrosative stress is a promising therapeutic strategy for HIV/AIDS is shown by studies of ART-treated macaques that were chronically infected with the HIV homolog SIVmac251 (35,96). In these studies, the combined inhibition of the Trx and GSH systems, obtained with auranofin and BSO coupled with a potent ART regimen, induced a functional cure, i.e., long-term, drug-free control in the absence of disease progression (120).…”

“…In these studies, the combined inhibition of the Trx and GSH systems, obtained with auranofin and BSO coupled with a potent ART regimen, induced a functional cure, i.e., long-term, drug-free control in the absence of disease progression (120). This state has been maintained for at least two years following the suspension of all drugs, with follow-up still ongoing (35). The mechanism of action of auranofin and BSO is likely three-fold (Figures 2 and 3).…”

“…Third, and perhaps most important, the drugs boost immunity against the conserved sequences of the viral capsid Gag protein (Figure 3). Indeed, when this immunity was inhibited by temporary depletion of CD8 + cells, the control of the virus was lost, thereby establishing causality (35).…”

“…GSH likely mediates its effects through posttranslational modification of proteins, particularly S-glutathionylation (32) and S-nitrosylation (33), and by protecting DNA from oxidative damage during replication (5, 7). Lymphocytes treated with inhibitors of both Trx and GSH systems exhibit impaired synthesis of DNA (10) and key proteins (e.g., α chain of the proliferation-related IL-2 receptor) and eventually die, while limited or incomplete effects are observed with either drug alone (34,35). Thus, the Trx and GSH pathways play important and complementary roles during lymphocyte activation and proliferation.…”

“…GSH depletion does not increase the prodifferentiation effect induced by TrxR inhibition (35), but may alter the intrinsic immunogenic properties of target cells, potentially by acting on death receptors. In this regard, treatment of drug-resistant leukemia cells with BSO induces the formation of the CD95 death-inducing signaling complex (128).…”