Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4+ memory T Cells

HIV-1-specific CD8 T cells can influence HIV-1 disease progression during untreated HIV-1 infection, but the functional and phenotypic properties of HIV-1-specific CD8 T cells in individuals treated with suppressive antiretroviral therapy remain less well understood. Here we show that a subgroup of HIV-1-specific CD8 T cells with stem cell-like properties, termed T memory stem cells (T SCM cells), is enriched in patients receiving suppressive antiretroviral therapy compared with their levels in untreated progressors or controllers. In addition, a prolonged duration of antiretroviral therapy was associated with a progressive increase in the relative proportions of these stem cell-like HIV-1-specific CD8 T cells. Interestingly, the proportions of HIV-1-specific CD8 T SCM cells and total HIV-1-specific CD8 T SCM cells were associated with the CD4 T cell counts during treatment with antiretroviral therapy but not with CD4 T cell counts, viral loads, or immune activation parameters in untreated patients, including controllers. HIV-1-specific CD8 T SCM cells had increased abilities to secrete interleukin-2 in response to viral antigen, while secretion of gamma interferon (IFN-␥) was more limited in comparison to alternative HIV-1-specific CD8 T cell subsets; however, only proportions of IFN-␥-secreting HIV-1-specific CD8 T SCM cells were associated with CD4 T cell counts during antiretroviral therapy. Together, these data suggest that HIV-1-specific CD8 T SCM cells represent a long-lasting component of the cellular immune response to HIV-1 that persists in an antigen-independent fashion during antiretroviral therapy but seems unable to survive and expand under conditions of ongoing viral replication during untreated infection. IMPORTANCE Memory CD8 T cells that imitate the functional properties of stem cells to maintain lifelong cellular immunity have been hypothesized for many years, but only recently have such cells, termed T memory stem cells (T SCM cells), been physically identified Cytotoxic T cell responses against HIV-1 are mounted early in the disease process and can be readily detected in the vast majority of untreated HIV-1-infected patients (1, 2). Evidence from a number of investigations, including animal models (3), immunogenetic associations (4, 5), human cohort studies (6, 7), and phylogenetic explorations of viral sequence evolution (8, 9), suggests that these cells can importantly modulate clinical HIV-1 disease progression, particularly in rare groups of patients who spontaneously control HIV-1 infection in the absence of treatment. In these patients, HIV-1-specific CD8 T cells typically exhibit a polyfunctional profile characterized by strong abilities to proliferate, secrete antiviral cytokines, and execute major histocompatibility complex (MHC) class I-restricted cytolysis through perforin and granzyme B (6, 10, 11). In contrast, HIV-1-specific CD8 T cells in persons with progressive untreated disease seem to have markedly weaker cytotoxic activities, upregulate markers of immune senescen...

Section: Discussionmentioning

confidence: 58%

Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Viganó

Negron

Ouyang

et al. 2015

“…HIV is currently incurable due to the presence of HIV integrated into the genome of resting cells, predominantly T CM , which constitute the major reservoir for HIV in patients on suppressive ART (36). In the setting of HIV reactivation from latency, the "shock and kill hypothesis" (37) predicts that HIV reactivation should cause reactivating cells to die.…”

Section: Apoptosis Resistance Of Cd4 Central Memory T Cells (T CM )mentioning

confidence: 99%

Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Cummins

Sainski

Dai

et al. 2016

105

Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Intense activity is focused on identifying a clinical intervention that results in a long term, drug free remission of HIV-1 infection. Latently infected CD4 T cells harbor transcriptionally silent, replication-competent HIV. Because these cells persist long term and are unaffected by current therapies, the cells represent an HIV reservoir that remains undiminished by current approaches. Pilot clinical trials have tested whether reactivation of HIV-1 from latency will decrease the number of cells containing HIV DNA due to viral cytopathic effect or immune-mediated clearance. The latency reversal agents vorinostat, panobinostat, and romidepsin result in HIV reactivation, as measured by increases in cell-associated HIV RNA, but no change in cell-associated HIV DNA, indicating that the reactivating cells do not die (1-4). Multiple ongoing studies are testing augmentation of the anti-HIV immune response in combination with viral reactivation as a strategy for HIV eradication.In an effort to inform these attempts to eradicate the HIV reservoir, we and others have been examining the mechanistic basis for HIV-induced killing of CD4 T cells under different circumstances of activation and HIV replication. Although numerous pathways may contribute to the decline of uninfected CD4 T cells during uncontrolled HIV infection (5), fewer pathways have been implicated in the demise of cells directly infected by HIV. After HIV attachment, at least three distinct pathways can initiate the death of infected cells: (i) RIG-I-mediated sensing of HIV RNA (6, 7), (ii) IFI-16 sensing of unintegrated HIV DNA (8, 9), and (iii) DNA-PK-sensing of HIV integrase nicking of host DNA (10). Once integrated into host DNA, HIV can remain in a latent state

“…infected cells under ART increases over time (15)(16)(17). To investigate the potential role of CD4 ϩ T SCM as a source of virus persistence in SIV-infected RM, we measured the level of total cellassociated SIV DNA in the four main memory CD4 ϩ T cell subsets (T SCM , T CM , T TM , and T EM ) that were flow sorted from both peripheral blood and lymph nodes.…”

Section: Constitution Of Cd4mentioning

confidence: 99%

“…The observation of high levels of HIV DNA in CD4 ϩ T SCM from HIV-infected individuals under ART, together with particular biological properties of these cells, such as high in vivo longevity, relative quiescence, and marked proliferative potential, led to the hypothesis that these cells represent a crucial contributor to virus persistence despite their relative low frequency (15). Indeed, two recent studies demonstrated that the duration of ART is directly correlated with the relative contribution of CD4 ϩ T SCM to the HIV DNA reservoir in HIV-infected individuals (15,16).…”

mentioning

confidence: 99%

Initiation of Antiretroviral Therapy Restores CD4 ⁺ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

Cartwright

Palesch

Mavigner

et al. 2016

Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4؉ T memory stem cells (T SCM ) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4؉ T SCM are preserved in number but show (i) a decrease in the frequency of CCR5 ؉ cells, (ii) an expansion of the fraction of proliferating Ki-67 ؉ cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4؉ T SCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4 ؉ CCR5 ؉ T SCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4؉ Ki-67 ؉ T SCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4؉ transitional memory (T TM ) and effector memory (T EM ) T cells declined ϳ100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4؉ T SCM and central memory T cells (T CM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4 ؉ T SCM homeostasis, and the observed stable level of virus in T SCM supports the hypothesis that these cells are a critical contributor to SIV persistence. IMPORTANCE Understanding the roles of various CD4؉ T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (T SCM ) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (T CM and T TM , respectively). CD4 ؉ T SCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4 ؉ T SCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as T TM and effector memory (T EM ). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4 ؉ T SCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir. Infection with pathogenic lentiviruses such as human and simian immunodeficiency viruses (HIV and SIV, respectively) significantly perturbs the homeostasis of the CD4 ϩ T cell compartment through preferential infection and depletion of memory CD4 ϩ T cells, which is the hallmark of progression to AIDS. While the availability of antiretroviral therapy (ART) has significantly reduced the mortality and ...