PubMed · 8105285
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B Durovni, M Pinto, M Schecter. 1993-10-23. AIDS case definitions in developing countries.. https://pubmed.ncbi.nlm.nih.gov/8105285/
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According to a previously proposed mathematical model, the pathogenesis of acquired immunodeficiency syndrome (AIDS) could be explained by two phenomena: direct human immunodeficiency virus (HIV) infection of CD4+ T-cell populations and ongoing generation and selection of HIV mutants with increasing replicative capacity. In the present paper, the results obtained with this model are described in more detail. For different values of biologically interpretable parameters, the model predicts very different patterns of CD4+ T-cell decline after primary infection. With the assumption of a variability of 10% to 25% of three parameters between infected individuals, the model yields a realistic distribution curve of the incubation period to AIDS.
The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.
The role of beta-chemokines in HIV infection was evaluated. The kinetics of regulated upon activation of normal T cell expressed and secreted, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein 1beta production by stimulated T lymphocytes did not differ substantially between HIV-infected (asymptomatic and with AIDS) and uninfected subjects. Maximal production of these beta-chemokines by activated peripheral blood cells was higher in the infected individuals than in uninfected individuals, but no significant difference was observed between healthy infected subjects and AIDS patients. Evaluation of the effect of HIV replication on beta-chemokine production indicated that acute infection of CD4+ T cells with non-syncytia-inducing (NSI) viruses generally increased beta-chemokine production two to eightfold, whereas with SI strains, it led to decreased production. The sensitivity of an individual's virus to beta-chemokine-mediated inhibition correlated with the NSI virus phenotype and a healthy clinical state. 50% of the AIDS patients, however, had NSI viruses that were sensitive to beta-chemokines. Finally, anti-beta-chemokine-neutralizing antibodies caused a more rapid release of HIV by CD4+ T cells naturally infected by NSI, but not SI, viruses indicating that endogenously produced chemokines can affect HIV production in culture. These findings suggest that beta-chemokines may affect HIV replication when an NSI virus is involved, but provide little evidence that they substantially influence HIV infection and pathogenesis.