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Pandemic HIV-1 is the result of zoonotic transmission of Simian immunodeficiency virus (SIV) from chimpanzee species Pan troglodytes troglodytes (SIVcpzPtt). The related Pan troglodytes schweinfurthii is the host of a similar virus, SIVcpzPts, which did not spread to humans. We tested these viruses with small-molecule capsid inhibitors (PF57, PF74, and GS-CA1) that interact with a binding groove in the capsid that is also used by CPSF6. While HIV-1 was sensitive to capsid inhibitors in cell lines, human macrophages and PBMCs, SIVcpzPtt was resistant in rhesus FRhL-2 cells and human PBMCs but was sensitive to PF74 in human HOS and HeLa cells. SIVcpzPts was insensitive to PF74 in FRhL-2 cells, HeLa cells, PBMCs, and macrophages, but was inhibited by PF74 in HOS cells. The truncated version of CPSF6 (CPSF6-358) inhibited SIVcpzPtt and HIV-1 while, in contrast, SIVcpzPts was resistant to CPSF6-358. Homology modelling of HIV-1, SIVcpzPtt, and SIVcpzPts capsids and binding energy estimates suggest that these three viruses bind similarly with the host proteins cyclophilin A (CYPA) and CPSF6 as well as the capsid inhibitor PF74. Cyclosporin A treatment, mutating the CYPA-binding loop in the capsid or CYPA-knockout eliminated SIVcpzPts' resistance to PF74 in HeLa cells. These experiments revealed that the antiviral capacity of PF74 is controlled by CYPA in a virus- and cell type-specific manner. Our data indicate that SIVcpz viruses can use infection pathways that escape the antiviral activity of PF74. We further suggest that the antiviral activity of PF74 capsid inhibitors depends on cellular cofactors. IMPORTANCE HIV-1 originated from SIVcpzPtt, but not from the related SIVcpzPts, and thus it is important to describe the molecular infection of SIVcpzPts in human cells to understand zoonosis of SIVs. Pharmacological HIV-1 capsid inhibitors (e.g., PF74) bind a capsid groove that is also a binding site for the cellular protein CPSF6. SIVcpzPts was resistant to PF74 in HeLa cells but sensitive in HOS, thus indicating cell-line specific resistance. Both SIVcpz viruses showed a resistance to PF74 in human PBMCs. Modulating the presence of cyclophilin A or its binding to capsid in HeLa cells overcame SIVcpzPts resistance to PF74. These results indicate that early cytoplasmic infection events of SIVcpzPts may differ between cell types and affect, in an unknown manner, the antiviral activity of capsid inhibitors. Thus, capsid inhibitors depend on the activity or interaction of currently uncharacterized cellular factors.

IntroductionUp to 30% of HIV infected patients who are receiving HAART do not exhibit a marked increase in the CD4+ T cell count. There is still a concern that immune recovery may not be complete once CD4+ T cells have decreased below 200 cells/μl. The objective is to assess CD4+ cell recovery in HIV+ patients with CD4 count below 200 cells/μl) at HAART initiation.MethodsThis was a retrospective cohort study among 110 HIV+ patients with initial CD4 count < 200 cells/μl. Baseline Age, sex, CD4 count and viral load were extracted from the patient’s database. After12 months of HAART; CD4 count was done using flow cytometry and viremia by COBAS AmpliPrep/COBAS TaqMan HIV-1 test v 2.0 technology.ResultsThe mean age of the respondents was 35 years; males being 57% and females were 43%. The mean CD4 count before HAART was 110.18 cells/μl whereas at 12 months of HAART; this was 305.01 cells/μl. Though some patients did not achieve a CD4 count of more than 200 cells/μl or a drop in viral load; there was a significant recovery of CD4+ cells (P value=0.000) and viremia following HAART (P value=0.001). Participants aged 18-30 years were likely to have less than 200 cells/μl CD4 count (46.4%) [OR=4.33; 95%CI: 1.29-14.59; P=0.018] than participants aged above 40 years (16.7%).ConclusionHAART was associated with viremia suppression but many patients failed to achieve a CD4 count >200 cells/μl. HAART before severe immunosuppression is a key factor for immune restoration among HIV+ patients.

Pandemic HIV-1, a human lentivirus, is the result of zoonotic transmission of SIV from chimpanzees (SIVcpz). How SIVcpz established spread in humans after spillover is an outstanding question. Lentiviral cross-species transmissions are exceptionally rare events. Nevertheless, the chimpanzee and the gorilla were part of the transmission chains that resulted in sustained infections that evolved into HIV-1. Although many restriction factors can repress the early stages of lentiviral replication, others target replication during the late phases. In some cases, viruses incorporate host proteins that interfere with subsequent rounds of replication. Though limited and small, HIVs and SIVs, including SIVcpz can use their genome products to modulate and escape some of these barriers and thus establish a chronic infection.