Evolution of SIVsm in humanized mice towards HIV-2.
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ABSTRACT:
SUBMITTER: Curlin J
PROVIDER: S-EPMC8162839 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:How SIV progenitors evolved into deadly HIV-1 and HIV-2 following initial cross-species transmission still remains a mystery. Here, we used humanized mice as a human surrogate system to evaluate SIVsm evolution into HIV-2. Increased viral virulence to human CD4+ T cells and adaptive genetic changes were observed during serial passages.
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Project description:HIV-2 is thought to have originated from an SIV progenitor native to sooty mangabeys. To model the initial human transmission and understand the sequential viral evolution, humanized mice were infected with SIVsm and serially passaged for five generations. Productive infection was seen by week 3 during the initial challenge followed by chronic viremia and gradual CD4+ T cell decline. Viral loads increased by the 5th generation resulting in more rapid CD4+ T cell decline. Genetic analysis revealed several amino acid substitutions that were nonsynonymous and fixed in multiple hu-mice across each of the 5 generations in the nef, env and rev regions. The highest rate of substitution occurred in the nef and env regions and most were observed within the first two generations. These data demonstrated the utility of hu-mice in modeling the SIVsm transmission to the human and to evaluate its potential sequential evolution into a human pathogen of HIV-2 lineage.
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Project description:Innate immune restriction factors represent important specialized barriers to zoonotic transmission of viruses. Significant consideration has been given to their possible use for therapeutic benefit. The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of cytidine deaminases are potent immune defense molecules capable of efficiently restricting endogenous retroelements as well as a broad range of viruses including Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV), Human Papilloma virus (HPV), and Human T Cell Leukemia virus (HTLV). The best characterized members of this family are APOBEC3G (A3G) and APOBEC3F (A3F) and their restriction of HIV. HIV has evolved to counteract these powerful restriction factors by encoding an accessory gene designated viral infectivity factor (vif). Here we demonstrate that APOBEC3 efficiently restricts CCR5-tropic HIV in the absence of Vif. However, our results also show that CXCR4-tropic HIV can escape from APOBEC3 restriction and replicate in vivo independent of Vif. Molecular analysis identified thymocytes as cells with reduced A3G and A3F expression. Direct injection of vif-defective HIV into the thymus resulted in viral replication and dissemination detected by plasma viral load analysis; however, vif-defective viruses remained sensitive to APOBEC3 restriction as extensive G to A mutation was observed in proviral DNA recovered from other organs. Remarkably, HIV replication persisted despite the inability of HIV to develop resistance to APOBEC3 in the absence of Vif. Our results provide novel insight into a highly specific subset of cells that potentially circumvent the action of APOBEC3; however our results also demonstrate the massive inactivation of CCR5-tropic HIV in the absence of Vif.
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Project description:The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.
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