HIV-2 Peptide

The discovery of the G-protein coupled-receptor (GPCR) CXCR4 as a major coreceptor of HIV-1 entry about three decades ago explained why the chemokine SDF-1/CXCL12 inhibits specific viral strains. The knowledge that RANTES, MlP-1α, and MlP-1β specifically inhibit other primary HIV-1 strains allowed the rapid discovery of CCR5 as second major viral coreceptor and explained why individuals with deletions in CCR5 are protected against sexual HIV-1 transmission. Here, we provide an update on endogenous ligands of GPCRs that act as endogenous inhibitors of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) entry. In addition, we summarize the development of optimized derivatives of endogenous GPCR ligands and their perspectives as antiviral agents and beyond. Finally, we provide examples for other endogenous peptides that may contribute to our innate immune defense against HIV-1 and other viral pathogens and offer prospects for preventive or therapeutic development.

HIV infection requires lifelong treatment with multiple antiretroviral drugs in a combination, which ultimately causes cumulative toxicities and drug resistance, thus necessitating the development of novel antiviral agents. We recently found that enfuvirtide (T-20)-based lipopeptides conjugated with fatty acids have dramatically increased in vitro and in vivo anti-HIV activities. Herein, a group of cholesterol-modified fusion inhibitors were characterized with significant findings. First, novel cholesterylated inhibitors, such as LP-83 and LP-86, showed the most potent activity in inhibiting divergent human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). Second, the cholesterylated inhibitors were highly active to inhibit T-20-resistant mutants that still conferred high resistance to the fatty acid derivatives. Third, the cholesterylated inhibitors had extremely potent activity to block HIV envelope (Env)-mediated cell-cell fusion, especially a truncated minimum lipopeptide (LP-95), showing a greatly increased potency relative to its inhibition on virus infection. Fourth, the cholesterylated inhibitors efficiently bound to both the cellular and viral membranes to exert their antiviral activities. Fifth, the cholesterylated inhibitors displayed low cytotoxicity and binding capacity with human serum albumin. Sixth, we further demonstrated that LP-83 exhibited extremely potent and long-lasting anti-HIV activity in rhesus monkeys. Taken together, the present results help our understanding on the mechanism of action of lipopeptide-based viral fusion inhibitors and facilitate the development of novel anti-HIV drugs.IMPORTANCE The peptide drug enfuvirtide (T-20) remains the only membrane fusion inhibitor available for treatment of viral infection, which is used in combination therapy of HIV-1 infection; however, it exhibits relatively low antiviral activity and a genetic barrier to inducing resistance, calling for the continuous development for novel anti-HIV agents. In this study, we report cholesterylated fusion inhibitors showing the most potent and broad anti-HIV activities to date. The new inhibitors have been comprehensively characterized for their modes of action and druggability, including small size, low cytotoxicity, binding ability to human serum albumin (HSA), and, especially, extremely potent and long-lasting antiviral activity in rhesus monkeys. Therefore, the present studies have provided new drug candidates for clinical development, which can also be used as tools to probe the mechanisms of viral entry and inhibition.

HIV-2, compared to HIV-1, elicits potent and broadly neutralizing antibodies, and uses a broad range of co-receptors. However, both sensitivity to neutralization and breadth of co-receptor use varies between HIV-2 isolates, and the molecular background is still not fully understood. Thus, in the current study, we have deciphered relationships between HIV-2 neutralization sensitivity, co-receptor use and viral envelope glycoprotein (Env) molecular motifs. A panel of primary HIV-2 isolates, with predefined use of co-receptors, was assessed for neutralization sensitivity using a set of HIV-2 Env-directed monoclonal antibodies and co-receptor indicator cell lines. Neutralization sensitivity of the isolates was analysed in relation target cell co-receptor expression, in addition to amino acid motifs and predicted structures of Env regions. Results showed that HIV-2 isolates were more resistant to neutralizing antibodies when entering target cells via the alternative co-receptor GPR15, as compared to CCR5. A similar pattern was noted for isolates using the alternative co-receptor CXCR6. Sensitivity to neutralizing antibodies appeared also to be linked to specific Env motifs in V1/V2 and C3 regions. Our findings suggest that HIV-2 sensitivity to neutralization depends both on which co-receptor is used for cell entry and on specific Env motifs. This study highlights the multifactorial mechanisms behind HIV-2 neutralization sensitivity.