Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.

CD4 T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat.

IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.

As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs.

Immune Modulation of HIV-1 Reservoir Size in Early-Treated Neonates.

Immune mechanisms that modulate human immunodeficiency virus-1 (HIV-1) reservoir size in neonates are poorly understood. Using samples from neonates who initiated antiretroviral therapy shortly after birth, we demonstrate that interleukin-8-secreting CD4 T cells, which are selectively expanded in early infancy, are more resistant to HIV-1 infection and inversely correlated with the frequency of intact proviruses at birth. Moreover, newborns with HIV-1 infection displayed a distinct B-cell profile at birth, with reduction of memory B cells and expansion of plasmablasts and transitional B cells; however, B-cell immune perturbations were unrelated to HIV-1 reservoir size and normalized after initiation of antiretroviral therapy.

Phenotypic signatures of immune selection in HIV-1 reservoir cells.

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4 T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses.

Immune correlates of HIV-1 reservoir cell decline in early-treated infants.

Initiation of antiretroviral therapy (ART) in infected neonates within hours after birth limits viral reservoir seeding but does not prevent long-term HIV-1 persistence. Here, we report parallel assessments of HIV-1 reservoir cells and innate antiviral immune responses in a unique cohort of 37 infected neonates from Botswana who started ART extremely early, frequently within hours after birth. Decline of genome-intact HIV-1 proviruses occurs rapidly after initiation of ART and is associated with an increase in natural killer (NK) cell populations expressing the cytotoxicity marker CD57 and with a decrease in NK cell subsets expressing the inhibitory marker NKG2A.