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In this study, 1219 HIV-uninfected, heterosexual adults in Botswana were randomly assigned to tenofovir–emtricitabine (TDF–FTC) or placebo. The TDF–FTC group had a lower incidence of HIV infection but increased rates of side effects, including a significant loss of bone density. Biomedical strategies to prevent sexual transmission of human immunodeficiency virus (HIV) remain limited. 1 In animal models, preexposure prophylaxis with tenofovir disoproxil fumarate (TDF) or with the combination of TDF and emtricitabine (TDF–FTC) can prevent infections with HIV or hybrid simian–human immunodeficiency virus after vaginal or rectal challenge. 2 , 3 In humans, daily preexposure prophylaxis with TDF–FTC has been shown to reduce transmission of HIV by 44% among men who have sex with men 4 ; however, the findings from studies in heterosexual populations have been mixed. 5 – 8 Botswana has the world's second highest prevalence of HIV infection, estimated in 2008 to be . . .

Four decades into the HIV pandemic, HIV-2 infection remains an underutilized comparative resource for HIV-1 cure research. HIV-2 is associated with lower plasma viral loads, slower CD4 + T-cell decline, and delayed disease progression in many individuals. Early studies attributed these features to intrinsic viral attenuation, pointing to differences in accessory protein function, transcriptional regulation, and reservoir size. However, accumulating molecular and epidemiological evidence challenges this interpretation. The transcriptional status of HIV-2 in vivo is not uniform across studies. Some studies report comparable viral RNA levels between HIV-1 and HIV-2 in CD4-matched individuals. In contrast, others find lower per-cell transcriptional output in HIV-2, suggesting that the degree of transcriptional restriction varies with cohort composition, disease stage, and measurement approach. Importantly, neither finding supports a model of uniform proviral silencing. This review examines the molecular biology, immune responses, and reservoir dynamics of HIV-2 infection, weighing evidence that both supports and challenges the view of HIV-2 as an attenuated comparator to HIV-1. The available data suggest that HIV-2 persistence involves regulated viral expression and ongoing, albeit attenuated, immune engagement, rather than transcriptional silence. However, the extent to which immune activation in HIV-2 is quantitatively or qualitatively distinct from that in HIV-1 remains incompletely resolved. HIV-2 does not provide a prescriptive cure blueprint, but it reveals a key biological constraint: ongoing viral transcription can coexist with prolonged immune containment. This finding argues against transcription-only approaches to HIV-1 remission and underscores the need for strategies that combine transcriptional modulation with sustained immune engagement.

Human immunodeficiency virus type 2 (HIV-2) is a lentivirus closely related to HIV-1 but exhibits distinct molecular and clinical features that influence viral infectivity and efficacy of antiretroviral therapy. The HIV capsid is a critical structural component with multifaceted roles during infection and mediates some of the observed divergence between HIV-1 and HIV-2. Unlike HIV-1, study of the HIV-2 capsid is limited and standard protocols for the in vitro assembly of HIV-1 capsid protein (CA) lattice structures have not been successfully translated to the HIV-2 context. This work identifies effective approaches for the assembly of the HIV-2 CA lattice and leverages this to biochemically characterize HIV-2 CA assemblies and mutant phenotypes. Our findings elaborate on the sensitivity of HIV-2 CA to chemical conditions and reveal that it assembles into a more varied spectrum of particle morphologies compared to HIV-1. Utilizing these assemblies, we tested the hypothesis that HIV-1 and HIV-2 employ divergent mechanisms to stabilize CA oligomer forms and investigate the effects of non-conserved substitutions at the CA inter-protomer interfaces. This work advances our understanding of the key biochemical determinants of HIV-2 CA assembly that are distinct from HIV-1 and may contribute to their divergent virological properties.

SERINC5 is a potent lentiviral restriction factor that gets incorporated into nascent virions and inhibits viral fusion and infectivity. The envelope glycoprotein (Env) is a key determinant for SERINC restriction, but many aspects of this relationship remain incompletely understood, and the mechanism of SERINC5 restriction remains unresolved. Here, we have used mutants of HIV-1 and HIV-2 to show that truncation of the Env cytoplasmic tail (ΔCT) confers complete resistance of both viruses to SERINC5 and SERINC3 restriction. Critically, fusion of HIV-1 ΔCT virus was not inhibited by SERINC5 incorporation into virions, providing a mechanism to explain how EnvCT truncation allows escape from restriction. Neutralization and inhibitor assays showed ΔCT viruses have an altered Env conformation and fusion kinetics, suggesting that EnvCT truncation dysregulates the processivity of entry, in turn allowing Env to escape targeting by SERINC5. Furthermore, HIV-1 and HIV-2 ΔCT viruses were also resistant to IFITMs, another entry-targeting family of restriction factors. Notably, while the EnvCT is essential for Env incorporation into HIV-1 virions and spreading infection in T cells, HIV-2 does not require the EnvCT. Here, we reveal a mechanism by which human lentiviruses can evade two potent Env-targeting restriction factors but show key differences in the capacity of HIV-1 and HIV-2 to exploit this. Taken together, this study provides insights into the interplay between HIV and entry-targeting restriction factors, revealing viral plasticity toward mechanisms of escape and a key role for the long lentiviral EnvCT in regulating these processes.

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options 1 – 3 . As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently 4 . Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection. A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.

Considering human immunodeficiency virus type 2 (HIV-2) phenotypic data and experience from HIV type 1 and from the follow-up of HIV-2—infected patients, a panel of European experts voted on a rule set for interpretation of mutations in HIV-2 protease, reverse transcriptase, and integrase and an automated tool for HIV-2 drug resistance analyses freely available on the Internet (http://www.hiv-grade.de).

Human immunodeficiency virus (HIV) type 2 (HIV-2) is less pathogenic than HIV-1. However, the factors responsible for the differences in pathogenicity are still not well defined. To investigate this issue, we performed infection of primary human monocyte-derived macrophages (MDMs) with individual HIV-1 or HIV-2 strains and compared the levels of M-CSF, a cytokine shown to promote HIV-1 infection and replication in our previous studies, and CXCL7, a chemokine identified as being expressed at levels correlated with HIV type by our preliminary gene-expression analysis. We tested several HIV-2 isolates able to replicate in human MDMs and observed that all of them induced the production of M-CSF at high levels similar to those previously established for HIV-1 infection. In addition, the production of M-CSF in MDMs infected with HIV-1 or HIV-2 isolates correlated with the extent of virus replication. In contrast to M-CSF, the chemokine CXCL7 was differentially expressed between MDMs infected with HIV-1 or HIV-2 isolates, as revealed by qPCR and ELISA testing. Together, these results suggest that M-CSF induction may play similar roles in promoting the replication of HIV-1 and HIV-2, while differential regulation of chemokine expression may be an important factor contributing to the differential pathogenicity of the two HIV subtypes.

Viral protein X (Vpx) is a unique accessory protein encoded by the genome of the human immunodeficiency virus type 2 (HIV-2) and lineages of the simian immunodeficiency virus of sooty mangabeys. So far, counteracting the cellular restriction factor SAMHD1 and mediating the efficient translocation of viral pre-integration complex have been recognized as key functions of Vpx; however, a thorough exploration of its effects on the cellular transcriptome and cytokine milieu has not yet been undertaken. In this study, we carried out the transcriptomic analysis of THP-1 cells and determined differential gene expressions induced by HIV-2 Vpx, utilizing vectors coding for the wild-type and K68-R70 functionally restricted proteins. Significantly altered genes were then validated and quantified through real-time quantitative PCR (qPCR); additionally, replication-competent virions were also used to confirm the findings. Moreover, we analyzed the effect of Vpx expression on the secretion of key cytokines in the medium of transfected cells. Our findings revealed that wild-type HIV-2 Vpx can significantly alter the expression of genes coding for helicases, zinc finger proteins, chaperons, transcription factors and proteins involved in DNA methylation. Differentially altered genes were involved in negative regulation of viral processes, the type I interferon-signaling pathway, DNA-template transcription, elongation, the positive regulation of interferon beta production and the negative regulation of innate immune response. Importantly, Vpx was also found to decrease the expression of HIV-1 Tat, possibly through the downregulation of a crucial splicing factor, required for the maturation of Tat. Additionally, studies on cellular cytokine milieu showed that this accessory protein induced key proinflammatory cytokines. Our study provides important information about the complex role played by HIV-2 Vpx in priming and taming the cellular environment to allow for the establishment of the infection.

Background During dual infection, HIV-1 and HIV-2 may infect the same cell, either simultaneously or sequentially. When these closely related lentiviruses co-infect, HIV-2 has been found to inhibit HIV-1 replication in vitro . In-patient infection data suggests that dual infection attenuates disease progression. Mechanisms underlying this inhibition have not been fully elucidated. Here, we assessed HIV-1 infectivity in presence or absence of HIV-2 in cell culture. Methods HIV-1 subtypes A, B, C, and CRF02_AG were used to infect TZM-bl reporter cells as single infections or as dual infections with HIV-2. Infectious titer concentrations were determined by cytopathic effect-based method (TCID50) and P24 ELISA was used to determine p24 concentration in supernatant. Infectivity was determined using luminescence assay, while qPCR was used to determine expression of cell-associated unspliced and multiply spliced HIV-1 RNA. HIV-1 cell free viral RNA (vRNA) levels were quantified in cell supernatants. Results Dual infections (simultaneous and sequential) resulted in reduced HIV-1 infectivity and replication relative to single infections. The reduction in infectivity varied among HIV-1 subtypes. Additionally, evaluation of expression levels of unspliced (us) and multiply spliced (ms) HIV-1 RNAs revealed lower expression of these RNA species in simultaneous dual infections for all the four subtypes tested. The same trend was observed for sequential dual infection with the exception of subtype B, which showed a slight increase in levels of usRNA. In both simultaneous and sequential dual infections, expression of msRNA was lower relative to HIV-1 mono-infection. Again, subtype B maintained the same trend as observed in usRNA during sequential dual infection. Despite the observed subtype specific variations, lower HIV-1 infectivity in dual infections coincided with reduced HIV-1 viral loads. Conclusion In summary, this study demonstrates a significant reduction in HIV-1 infectivity in the presence of HIV-2. Reduced infectivity was characterized by lower viral loads and coincided with reduced HIV-1 transcription and splicing. These findings pave way for future mechanistic studies to understand the drivers of reduced infectivity in dual infection.

Resting CD4 + T cells are resistant to HIV-1 infection, but the underlying reasons for this lack of permissiveness have not been clear. Oliver Fackler and colleagues now report that SAMHD1, the deoxynucleoside triphosphate triphosphohydrolase responsible for restriction of HIV-1 infection in myeloid cells, also restricts infection of resting CD4 + T cells. The findings shed new light on the mechanisms of cellular and molecular regulation of HIV-1 infection. Unlike activated CD4 + T cells, resting CD4 + T cells are highly resistant to productive HIV-1 infection 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Early after HIV-1 entry, a major block limits reverse transcription of incoming viral genomes. Here we show that the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 prevents reverse transcription of HIV-1 RNA in resting CD4 + T cells. SAMHD1 is abundantly expressed in resting CD4 + T cells circulating in peripheral blood and residing in lymphoid organs. The early restriction to infection in unstimulated CD4 + T cells is overcome by HIV-1 or HIV-2 virions into which viral Vpx is artificially or naturally packaged, respectively, or by addition of exogenous deoxynucleosides. Vpx-mediated proteasomal degradation of SAMHD1 and elevation of intracellular deoxynucleotide pools precede successful infection by Vpx-carrying HIV. Resting CD4 + T cells from healthy donors following SAMHD1 silencing or from a patient with Aicardi-Goutières syndrome homozygous for a nonsense mutation in SAMHD1 were permissive for HIV-1 infection. Thus, SAMHD1 imposes an effective restriction to HIV-1 infection in the large pool of noncycling CD4 + T cells in vivo . Bypassing SAMHD1 was insufficient for the release of viral progeny, implicating other barriers at later stages of HIV replication. Together, these findings may unveil new ways to interfere with the immune evasion and T cell immunopathology of pandemic HIV-1.