Whole genome studies reported a strong association between a specific SNP of the HLA-C gene and HIV-1 viral load (Fellay 2007). Patients with higher HLA-C expression had slower progression to AIDS and better control of HIV-1 viremia (van Manen 2009), likely due to a better antigen presentation to T-cells. Recent findings suggest that this association may be the consequence of strong linkage disequilibrium between determinants for HIV-1 control, making difficult the identification of casual variants (Trachtenberg 2009, Corrah 2011). Host cell proteins are selectively incorporated in HIV-1 virions and modulate viral infectivity. HIV-1 induces downregulation of HLA-A and -B, but not -C, probably to prevent NK recognition and lysis of HIV-1 infected cells (Williams 2002). We reported that virus particles missing HLA-C are less infectious and demonstrated a specific association with gp120 (Matucci 2008). HLA-C thus can influence HIV-1 infection not only by regulating the immune response, but also via a direct effect on virus replication and infectivity, as well as through a decreased sensitivity to neutralizing antibodies (Cosma 1999). Different studies showed that anti-MHC-I antibodies elicited by experimental vaccines are associated with protection (Chan 1995) and that anti-HLA antibodies are present in LTNP (Lopalco 2000). Alloimmunization has been proposed as a vaccinal strategy (Lehner 2000), as well as combined immunization with HLA and HIV-1 antigens (Morner 2011). Understanding the details of HLA-C interaction with gp120 has important implications to design novel immunogens and compounds that can reduce infectivity.
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