Comparative study of Human Immunodeficiency Virus type 1 and type 2 single and dual infections
Authors:   , Yapo Assi Vincent De Paul 
Published: December 2023

Human Immunodeficiency Virus (HIV) type 1 and type 2 are two related lentiviruses that have strikingly divergent features in terms of transmission rates, distribution, pathogenesis, and clinical outcomes. In places where both viruses coexist, individuals infected with HIV-2 showed less susceptibility to incident HIV-1 infection. Moreover, dual infected individuals may have better outcomes compared to their HIV-1 counterparts. Attempts to decipher the mechanisms underlying these stark differences between HIV-1 and HIV-2 have been underway since the discovery of these two infections in the 1980s. Many factors have been proposed including SAM and HD domain containing deoxynucleotides triphosphate triphosphohydrolase 1 (SAMHD1) and Vpx, type I interferon (IFN) responses, CD8+ cytotoxic T cells responses, and HIV-2 specific antibody responses. We studied the kinetics of HIV-1 and HIV-2 single infection with fluorescent in situ hybridization (FISH) coupled with microscopy, and with qPCR. Our data indicated that HIV-1 infection in TZM-bl cells proceeded quickly upon viral entry. It led to a faster integration into the host cell genome, and to higher rates of transcription with transcriptional bursts than those observed with HIV-2. On the other hand, HIV-2 was slower with a roughly two hours delay in reverse transcription completion and integration relative to HIV-1. Analysis the state of the chromatin around HIV-1 and HIV-2 long terminal repeat (LTR) promoters showed that both LTRs had similar active chromatin marker H3K9me2 levels, and should be equally accessible to host transcription machinery. Host RNA polymerase II (RNAP II) occupancy analysis at each LTR promoter start sites showed less occupancy in the case of HIV-2 LTR. Secondly, we demonstrated that under laboratory conditions, HIV-1 and HIV-2 can infect the same target cell, a phenomenon known as dual infection. We found that when HIV-2 infects the target cell at the same time or before HIV-1 infection, HIV-1 infection is inhibited. Under these conditions, inhibition was non-reciprocal meaning that HIV-2 inhibits HIV-1 but the reverse was not true. It was also dose-dependent as the higher the HIV-2 multiplicity of infection (MOI) used the higher the inhibition of HIV-1 infection. We identified two mechanisms. The first mechanism involved type I IFN responses that had broad effects on gene expression in the target cell. We also identified a second mechanism that was selective for HIV-1, other retroviruses such as Murine Leukemia Virus (MLV) and Rous Sarcomas Virus (RSV) were not sensitive to HIV-2-mediated inhibition. HIV-1 selective inhibition was mediated through HIV-2 TAR. This latter mechanism used a block of HIV-1 LTR-driven transcription at the elongation phase by decreasing HIV-1 Tat protein availability through competition between HIV-1 TAR and HIV-2 TAR for HIV-1 Tat protein. Mapping the sequences of HIV-2 TAR element required for the downmodulation showed that any two-stem loop structure including the HIV-2 stem loop 2 was inhibitory to HIV-1 infection.