Genetic and Immunological Factors Involved in Natural Resistance to HIV-1 Infection

Abstract

Infection with Human immunodeficiency virus type-1 (HIV-1) induces severe alterations of the immune system leading to an increased susceptibility to opportunistic infections and malignancies. However, exposure to the virus does not always results in infection. Indeed, there exist individuals who have been repeatedly exposed to HIV-1 but do not exhibit clinical or serological evidence of infection, known as exposed seronegative individuals. Many studies have focused on the different mechanisms involved in natural resistance to HIV-1 infection, and have reported several factors associated with this phenomenon, including the presence of genetic polymorphisms in the viral coreceptors, innate and adaptive immune cells with particular phenotypic and functional features, and molecules such as antibodies and soluble factors that play an important role in defense against infection by HIV-1. The study of these factors could be the key for controlling this viral infection. This review summarizes the main mechanisms involved in resistance to HIV-1 infection.

Keywords: HIV-1 (Human immunodeficiency virus type-1); antibodies; exposed seronegative individuals; natural resistance; polymorphisms; soluble factors..

Fig. (1)

Mechanisms of resistance involved in the protection against HIV-1-infection and AIDS-progression. Target cells have polymorphisms in CCR5 gene or other alternative viral coreceptors, such as CCR2 (1), all of them induce low or non-expression of these coreceptors, inhibiting viral entry. This step can be also blocked by high production of the coreceptors ligands, MIP-1α/β, RANTES and SDF-1 (2). Elevated spontaneous and inducible apoptosis of monocytes and other HIV-1-target cells has been reported in ESNs (3). Increased release of soluble antiviral factors APOBEC3G, CAF, α and β- defensins, type I IFN, LIF, MIP-1α/β, RANTES, RNases, SDF-1, SLPI, TRIM5α and elafin block viral entry or replication (4). ESNs individuals exhibit high activity in NK cells and DCs. NK cells express KIR3DS1 and KIR3DL1 related to cell activation (5) and are able to produce IFN-γ (6). DCs also express the co-stimulatory molecules CD80 and CD86 (7) and produce IFN-α (6). Type I IFN induces HLA expression, apoptosis of infected cells, production of antiviral molecules, and block viral replication. The specific immune response is characterized by the presence of CTLs restricted to HLA-B57 and –B27, presenting immunodominant peptides (8), production of cytokines such as RANTES, MIP-1β, IL-6, IFN-γ, TNF-α and β and IL-2 that increase the immune response and expression of markers associated with T cell activation (9). B-cells produce neutralizing IgA antibodies, detectable in serum, mucosa and breast milk (10).