Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.

Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses.

Irreversible Inhibition of DNMT3A by an N-Mustard Analog of S-Adenosyl-L-Methionine.

DNA methylation, an important epigenetic modification, is catalyzed by DNA methyltransferases and is essential in the regulation of gene expression. Here, the utility of an N-mustard analog designed to mimic the native methyl donor, S-adenosyl-L-methionine (SAM), was explored with the DNA methyltransferase 3A catalytic domain (DNMT3AC). In lieu of the expected analog transfer to DNA, methyltransferase activity was instead inhibited in a concentration dependent manner.

Vedolizumab and ART in recent HIV-1 infection unveil the role of α4β7 in reservoir size.

BACKGROUNDWe evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the effect of α4β7 on the HIV-1 reservoir size.METHODSParticipants started ART with monthly vedolizumab infusions, and ATI was performed at week 24.

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).

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.

Lymph node dendritic cells harbor inducible replication-competent HIV despite years of suppressive ART.

Although gut and lymph node (LN) memory CD4 T cells represent major HIV and simian immunodeficiency virus (SIV) tissue reservoirs, the study of the role of dendritic cells (DCs) in HIV persistence has long been limited to the blood due to difficulties to access lymphoid tissue samples. In this study, we show that LN migratory and resident DC subpopulations harbor distinct phenotypic and transcriptomic profiles. Interestingly, both LN DC subpopulations contain HIV intact provirus and inducible replication-competent HIV despite the expression of the antiviral restriction factor SAMHD1.

Progressive transformation of the HIV-1 reservoir cell profile over two decades of antiviral therapy.

HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated.