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HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals.

Clearing a path for an HIV cure: Curing HIV is more feasible if we better understand the formation of the latent viral reservoir. Leyre et al. studied longitudinal blood and tissue samples during acute HIV infection. The large pool of infected cells present at early stages did not survive antiretroviral treatment. Infected cells at later stages were more prevalent in lymphoid tissues than in blood. These results show that most infected targets are cleared with early treatment, but HIV+ cells that remain after a certain stage are more likely to persist. These persistent cells are the ones that will need to be eradicated for a cure to be achieved. The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4+ T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist. [ABSTRACT FROM AUTHOR]

Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14+ monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4+ T-cell contamination, 0.06%), and the levels of CD4+ T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4+ T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4+ T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4+ T cells. [ABSTRACT FROM AUTHOR]

The article presents a study that analyzed the quality of HIV-specific CD8+ T cell responses emerging in the earliest stages of acute infection and assessed whether these responses could control viral replication and HIV reservoir seeding after antiretroviral therapy initiation. Topics discussed include HIV-specific CD8+ T cell expansion in the early stages of acute HIV-1 infection and loss of cytokine secretion and survival potential ofHIV-specific CD8+T cells during acute HIV infection.

HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. [ABSTRACT FROM AUTHOR]

Steroidal alkaloid cortistatin is a promising marine natural compound isolated from marine sponges Corticium simplex. Experimental studies and clinical evidence have shown that cortistatin and its derivatives have a curative effect in patients with autoimmune disorders, HIV infection and several types of cancer. The objective of our study was to examine the potential cancer-related therapeutic objectives of Cortistatin using a network pharmacology method, which is a computational approach, including inverse pharmacophore research, enrichment analysis, molecular docking and dynamics study. Systematic protocol also involves the assessment of ADMET parameters to define the pharmacokinetic profile of cortistatin. Inverse pharmacophore search method was used for computational target fishing and target proteins were ranked based on the graph theory approach. Cancer target proteins, namely HSP90, EGFR, CDK2, MMP13, MAPK13, AR, ESR1, PTPN11 and SRC, were classified as top-ranking proteins according to graph theory parameters, namely MCC, DMNC, MNC, Degree(Local-based methods), EPC, Bottleneck, Eccentricity, Closeness, Radiality, Betweenness, Stress(Global-based methods) and Clustering Coefficient. Enrichment assessment established on Gene Ontology and pathway analysis of these proteins that play a vital role in cancer pathways, FaxO Signalling pathways, Ras Signalling pathways and tyrosine metabolism. Molecular docking and dynamic simulation studies of cortistatin with proposed target proteins were found to be stable and conformers generated after 3ns were consistent with stable inter-molecular interactions. The current study summarized here would provide a broad perspective on the therapeutic potential of cortistatin and provide new insights into the future development of cancer therapy strategies. [ABSTRACT FROM AUTHOR]

An efficient stereoselective synthesis 3α- and 3β-aminoandrostan-17-one and 3α-amino dehydroepiandrosten-17-one based on a Mitsunobu reaction has been developed, using azide as the ammonia equivalent. All the products were isolated in high yield. [ABSTRACT FROM AUTHOR]