Changes in biologic phenotype of human immunodeficiency virus during treatment of patients with didanosine.

Progression to AIDS in patients harboring human immunodeficiency virus type-1 (HIV-1) isolates expressing a syncytium-inducing (SI) phenotype is faster than in those in whom the virus expresses a non-SI (NSI) phenotype. Zidovudine monotherapy does not appear to alter this outcome. To examine the role of didanosine (ddI) monotherapy in phenotype expression, HIV-1 isolates from 73 patients receiving ddI for up to 72 weeks were analyzed. After 12 weeks, the number of isolates expressing an NSI phenotype was 29% higher than at the start of treatment. Patients receiving high-dose ddI (375 mg twice daily) were significantly more likely to express the NSI phenotype at 12 weeks than patients who received low-dose ddI (100 mg twice daily), even after adjustment for phenotype and CD4 cell count at baseline, suggesting that ddI may be selective against the faster-replicating virus. ddI at 375 mg twice daily significantly increases the probability of an NSI phenotype over the short term in patients with advanced HIV disease.

Primary structure of the V3 region of gp120 from sequential human immunodeficiency virus type 1 isolates obtained from patients from the time of seroconversion.

V3 loop sequences were compared from 5 human immunodeficiency virus type 1 (HIV-1)-infected patients over time. Three patients remained asymptomatic and 2 became symptomatic with large decrease in CD4 cell counts. The patient isolates were previously evaluated for phenotypic and antigenic properties and had different sensitivities to serum neutralization and changes in phenotype. This study showed a number of amino acid changes for the 2 symptomatic patients, each of whom progressed to AIDS during the study. The only amino acid substitution consistently associated with reduced CD4 cell counts, cytopathic effect, and progression to AIDS was Arg at position 11. Specific amino acid changes could not be correlated with increasing serum neutralization resistance or cytotropism changes. Increased loop charge was associated with a switch from macrophage to T cell tropism and a decrease in the number of CD4 cells. The study shows the importance of naturally occurring mutations in the V3 loop in controlling the biologic properties of HIV-1.

Productive in vitro infection of human umbilical vein endothelial cells and three colon carcinoma cell lines with HIV-1.

The objective of this study was to assess the ability of HIV-1 to establish an in vitro infection of primary human umbilical vein endothelial cells (HUVEC). The HUVEC and colon carcinoma cell lines were inoculated with different isolates of HIV-1 (HIV-1SF2, HIV-1Mck and HIV-1LAI) and productive viral infection was assessed by both the detection of p24 core antigen in the culture supernatants and the presence of specific spliced HIV mRNA. The infection which was detected in the inoculated HUVEC and all the colon carcinoma cell lines could not be blocked using an antibody targeted against the CD4 receptor. Furthermore, the HIV-inoculated HUVEC secreted elevated levels of IL-6 and this increase was found to be proportional to the size of the viral inoculum. No changes in the production of IL-1 beta, TNF-alpha, IFN-alpha and IFN-gamma were detected following HIV infection. The colon carcinoma cells, however, did not secrete increased levels of these cytokines following HIV-1 inoculation. These results confirm that non-CD4 expressing cells, such as endothelial cells and certain colon epithelial cells, serve as targets and reservoirs for HIV. Moreover, the production of IL-6 by HIV-infected endothelial cells may be a contributing factor to the aberrant immunoregulation associated with HIV infection in vivo.