Variability in the natural history of HIV-1 infection has been repeatedly associated with genetic variants in the betachemokine receptor 5 (CCR5) locus. While CCR5 coding sequences have demonstrated relatively limited variation, sequences of its promoter appear polymorphic in all major populations. Our studies revealed five major CCR5 promoter alleles with distributions that differed widely among the four distinct ethnic groups from Kigali, Rwanda and Bronx, New York. In particular, promoter allele P*0103 (G 59029 -T 59353 -T 59356 -A 59402 -C 59653 ) was largely restricted to black subjects. The promoter allele P*0202 (A 59029 -C 59353 -C 59356 -A 59402 -T 59653 ) was tightly linked to the slightly less frequent CCR2b-64I, a variant of the CCR2b gene, which is about 12.7 kbp upstream from the promoter region. Another closely related promoter allele P*0201 (A 59029 -C 59353 -C 59356 -A 59402 -C 59653 ) exclusively carried the far less common CCR5-⌬32, a 32-bp deletion in the CCR5 coding sequence 2 kbp downstream from the promoter. The homozygous P*0201/*0201 genotype can be predicted as a risk factor for more rapid disease progression. Among human, chimpanzee, pig-tailed macaque, and sooty mangabey promoter allelic sequences, the apparent ancestral lineage of the promoter sequence (G 59029 -T 59353 -C 59356 -A 59402 -C 59653 = human P*0102) was highly conserved across the primate species analyzed here while P*0201 and P*0202 arose more recently than the other three major alleles. Further effort to establish the mechanism by which CCR chemokine receptor polymorphisms govern the initiation and pathogenesis of primate lentivirus infection apparently requires fully detailed genotypic characterization of the affected populations.
The immunologic and virologic status of a chimpanzee inoculated with multiple isolates of the human immunodeficiency virus type 1 (HIV-1) were assessed over 57 months to determine whether prolonged thrombocytopenia and CD4+ lymphocytopenia observed in the animal might be associated with long-term HIV infection. Although the chimpanzee showed no signs of disease, it lost both CD4+ (as low as 134 cells/microliter) and CD8+ lymphocytes approximately 30 months after initial infection, followed by thrombocytopenia that has persisted for greater than 2 years. Lymphopenia and thrombocytopenia were preceded by or coincided with the appearance of antibodies cross-reactive with histone H2B and decreased levels of complement component C4; an eightfold decrease in HIV-specific antibody titers; the inability of CD8+ lymphocytes to suppress virus replication; impaired proliferative responses to T cell mitogens; and the isolation of cell-free HIV from plasma. These data suggest that, given sufficient time, HIV-infected chimpanzees may develop disease.
Following exposure of the rectal or vaginal mucosa to cell-free SIVsmmPBj14, four male and two female pig-tailed macaques developed a characteristic acute disease, including mucoid diarrhea, lymphopenia, and anorexia. Two macaques infected by the rectal route died within 14 days, and one female died of an AIDS-like disease at five months after inoculation. The three other animals have survived more than nine months, but all are exhibiting lymphadenopathy, thrombocytopenia, and progressive declines in percentages and numbers of CD4+ lymphocytes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.