The role of viral phenotype and CCR-5 gene defects in HIV-1 transmission and disease progression

Abstract

Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding to both CD4 (ref, 1, 2) and to one of the chemokine receptors recently discovered to act as coreceptors. Viruses that infect T-cell lines to form syncytia (syncytium-inducing, SI) are frequently found in late-stage HIV disease and utilize the chemokine receptor CXCR-4; macrophage-tropic viruses are non-syncytium-inducing (NSI), found throughout disease and utilize CCR-5 (ref. 3-11). We postulated that CCR-5 gene defects might reduce infection risk in seronegative subjects and prolong AIDS-free survival in seropositive subjects with NSI but not SI virus. Homozygous (delta ccr5/delta ccr5) and heterozygous (CCR5/delta ccr5) CCR-5 deletions (delta ccr5) were found in 7 (2.7%) and 51 (19.5%), respectively, of 261 seronegative subjects from the San Francisco Men's Health Study. CCR-5/delta ccr5 genotype was identified in 33 of 172 (19.2%) nonprogressors and 25 of 234 (10.7%) progressors from the seropositive arm of this cohort. The delta ccr5 allele conferred a significant protective effect against HIV-1 infection (P = 0.001) and a survival advantage against disease progression (P = 0.02). Although both progressing and nonprogressing CCR5/delta ccr5 subjects were identified, a distinct survival advantage was shown for those with NSI virus (P < 0.0001). Thus, the protective effect of delta ccr5 against disease progression is lost when the infecting virus uses CXCR-4 as a coreceptor.

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

“…1,2 Persons with a homozygous 32 base-pair deletion in the CCR-5 gene, resulting in a truncated protein that remains within the cell, are highly resistant to HIV-1 infection. [9][10][11][12][13][14] This alteration does not affect the health of homozygous carriers, indicating that its functions are dispensable. [9][10][11][12][13][14] Thus, CCR-5 affords an attractive therapeutic target, especially for patients in the early stage of infection.…”

Global human genetics of HIV-1 infection and China

“…Significant studies in the past few years have also demonstrated that innate immunity including genetic polymorphisms in host genes can affect the risk for HIV-1 infection and disease progression (Tab. 1), although the effect of these alleles has been inconsistent [32,[45][46][47][48][49][50][51][52][53][54][55] (reviewed in [56]). Here, we review global and Chinese studies on human genetic polymorphisms and their association with HIV-1 infection.…”

“…individuals that are CCR5-32 homozygotes (people who inherited the CCR5-32 from both parents) are resistant to HIV-1 infection, indicating that genotype CCR5-32 is highly protective against HIV-1 infection [45][46][47][48][49][50]54]. However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68].…”

“…However, this protection is not absolute because rare individuals homozygous for CCR5-32 are infected with HIV-1 strains that may utilize another co-receptor, such as CXCR4 [64][65][66][67][68]. Furthermore, homozygous CCR5-32 is found only in 1% of the general population of Caucasians, but not in Africans, Asians or other ethnic groups [45][46][47][48][49][50]54], and the majority of highly exposed yet uninfected individuals have two normal CCR5 alleles (called wild-type, or wt). Similarly, we found CCR5-32 homozygotes in 1.0% (7 out of 705) of HIV-1 seronegative individuals and 3.1% (3 out of 97) of ES.…”

“…CCR5-32 heterozygotes (people who inherited the CCR5-32 allele from one parent and a functional CCR5 allele from the other parent) are susceptible to HIV-1 infection; most studies have not supported an association of the heterozygous CCR5-32 genotype with reduced HIV-1 transmission risk for adult and pediatric populations [47][48][49][69][70][71][72][73]. However, our recent study suggests that individuals with the combination of heterozygous CCR5-32 and P1 CCR5 promoter genotype (see below) are relatively resistant to HIV-1 transmission [74].…”