In 1996 a series of landmark studies were published which established the role of specific chemokine coreceptor proteins that enable viral invasion of T cells expressing CD4. For the main viral strains of HIV-1 transmitted through sexual activity, denoted R5 strains (Box 14.3), the CC chemokine receptor CCR5 (CC-CKR-5) was identified as the major host coreceptor protein (Alkhatib et al. 1996; Choe et al. 1996; Deng et al. 1996; Doranz et al. 1996; Dragic et al. 1996). CCR5 is necessary for fusion of the viral envelope protein with the host cell membrane, allowing entry of the viral core into the cytoplasm of the cell (Fig. 14.4). In the same year, a mutation in the gene encoding CCR5 was found to be responsible for the resistance of a small minority of individuals of European descent to infection by HIV-1.
A number of research groups had documented the apparent resistance of a minority of individuals to infection by HIV-1 despite repeated high risk exposures to the virus (Rowland-Jones et al. 1995). Study of this extreme phenotype was to prove rewarding. Paxton and colleagues analysed in detail 25 people with a history of multiple high risk sexual exposures who remained free of HIV-1 infection based on available testing at the time using an enzyme-linked immunosorbent assay (ELISA) and diagnostic polymerase chain reaction (PCR) (Paxton et al. 1996). The T lymphocytes expressing CD4 in these individuals were significantly less susceptible to infection by different primary isolates of the virus than non-exposed controls. This was most evident for cells derived from two men, designated EU2 and EU3, that required a 1000-fold more virus to establish infection in vitro. These individuals had reported sex with multiple HIV-1 infected partners yet had remained uninfected. The genetic basis for this resistance was found to relate to CCR5 (Liu et al. 1996). CCR5 cDNA was amplified and cloned into an expression vector then cotransfected with a CD4 expression vector. This showed that the CCR5 constructs prepared using cDNA derived from EU2 and EU3 were inactive.
Gene products Allele(s) Effect
Barriers to retroviral infection TRIM5a ABOBEC3G
Influence on HIV-1 infection Coreceptor/ligand
■ CCR5 A32 homozygous l Infection
■ CCL2, CCL 7, CCL11 T Infection Cytokine
IL-10 5' A dominant l Infection
SPRY species specific Infection resistance, capsid specific
Polymorphisms Infection resistance, hypermutation
Influence on development of AIDS
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