Human immunodeficiency virus type 2: pathogenesis and antiretroviral therapy

Human immunodeficiency virus type1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) have been identified as hither unknown primate members of the Lentivirinae subfamily of the family Retroviridae in 1983, 1986 and 1985 respectively, HIV-1 and HIV-2 were identified as the causative agents of the newly emerging acquired immunodeficiency syndrome (AIDS) of humans (1-3) and SIV was shown to cause AIDS in certain primate species, HIV-1 is clearly an emerging virus, which is expected to have infected between 30 and 40 million people by the year 2000, Although lentiviruses of different animal species share many biological features, the natural course of the disease they cause in their respective host species varies considerably, Table 1 summarises the currently known lentiviruses and their pathogenic characteristics in different host species, Elucidation of the differences in the pathogenesis of infection with different lentiviruses as well as the underlying mechanisms, may be expected to lead to a better understanding of the course of the natural infection with any of these viruses and will provide new tools for the development of intervention strategies, Most notably, the understanding of the marked differences between the natural diseases caused by the respective primate lentiviruses HIV-1, HIV-2 and SIV, may lead to the identification of new therapeutic and preventive measures for AIDS in humans, which in the light of the current pandemic spreading of this disease are more needed than ever

In vitro replication capacity of HIV-2 variants from long-term aviremic individuals

AbstractTo establish whether efficient suppression of virus replication in HIV-2-infected individuals is associated with low replicative capacity of HIV-2, replication kinetics of HIV-2 variants from long-term aviremic individuals was analyzed and compared with that of the relatively slow-replicating HIV-1 variants from asymptomatics and long-term nonprogressors (AS/LTNP). On average, HIV-2 from aviremic individuals had lower replication rates than HIV-1 variants from AS/LTNP in cells of 8 donors (0.45 log10 [range 0.14–0.77] vs. 0.58 log10 [range 0.32–0.99] pg RT/ml/day, P = 0.036). The relatively low replication rate of HIV-2 compared to HIV-1 variants was not related to different sensitivities to inhibition by CD8+ T cells or different degrees of infectivity. HIV-2 replication rates increased with progressive infection and with switch from CCR5 to CXCR4 usage.The relatively low replicative capacity of HIV-2 variants from aviremic individuals likely contributes to the low viral load and benign course of infection in these individuals

In vitro replication capacity of HIV-2 variants from long-term aviremic individuals

To establish whether efficient suppression of virus replication in HIV-2-infected individuals is associated with low replicative capacity of HIV-2, replication kinetics of HIV-2 variants from long-term aviremic individuals was analyzed and compared with that of the relatively slow-replicating HIV-1 variants from asymptomatics and long-term nonprogressors (AS/LTNP). On average, HIV-2 from aviremic individuals had lower replication rates than HIV-1 variants from AS/LTNP in cells of 8 donors (0.45 log10 [range 0.14-0.77] vs. 0.58 log10 [range 0.32-0.99] pg RT/ml/day, P = 0.036). The relatively low replication rate of HIV-2 compared to HIV-1 variants was not related to different sensitivities to inhibition by CD8+ T cells or different degrees of infectivity. HIV-2 replication rates increased with progressive infection and with switch from CCR5 to CXCR4 usage. The relatively low replicative capacity of HIV-2 variants from aviremic individuals likely contributes to the low viral load and benign course of infection in these individuals

CD4 T cells remain the major source of HIV-1 during end stage disease.

OBJECTIVE: To assess the source of HIV-1 production in lymphoid tissue biopsies from HIV-infected patients, with no prior anti-retroviral protease inhibitor treatment, with a CD4 cell count > 150 x 10(6)/l (group I) or < 50 x 10(6)/l (group II), co-infected with Mycobacterium tuberculosis or Mycobacterium avium complex. DESIGN AND METHODS: Lymphoid tissue biopsies from 11 HIV-1-infected patients, taken for diagnostic purposes, were studied by HIV-1 RNA in situ hybridization and immunohistochemistry. RESULTS: Patients of group I showed well organized granulomas, in contrast with patients of group II, in which granuloma formation was absent. HIV-1 RNA-positive cells in group I patients were found mainly around the granulomas, whereas in group II HIV-1-producing cells were confined to areas with remaining intact lymphoid tissue. Despite the abundant presence of macrophages, the productively infected HIV-1-positive cells in both groups were almost exclusively CD4 T cells. CONCLUSION: In contrast with previously published data, CD4 T cells appear to remain the major source of HIV-1 production in end-stage disease

Coreceptor usage of human immunodeficiency virus type 2 primary isolates and biological clones is broad and does not correlate with their syncytium-inducing capacities

Entry of human immunodeficiency virus type 1 (HIV-1) into target cells is mediated by binding of the surface envelope glycoprotein to the CD4 molecule. Interaction of the resulting CD4-glycoprotein complex with alpha- or beta-chemokine receptors, depending on the biological phenotype of the virus, then initiates the fusion process. Here, we show that primary HIV-2 isolates and biological clones, in contrast to those of HIV-1, may use a broad range of coreceptors, including CCR-1, CCR-3, CCR-5, and CXCR-4. The syncytium-inducing capacity of these viruses did not correlate with the ability to infect via CXCR-4 or any other coreceptor. One cell-free passage of the intermediate isolates in mitogen-stimulated, CD8+ cell-depleted peripheral blood mononuclear cells resulted in the outgrowth of variants with CCR-5 only, whereas the coreceptor usage of late and early isolates did not change. Since HIV-2 is less pathogenic in vivo than HIV-1, these data suggest that HIV pathogenicity in vivo is not directly related to the spectrum of coreceptors used in in vitro systems

Broadening of coreceptor usage by human immunodeficiency virus type 2 does not correlate with increased pathogenicity in an in vivo model.

The pathogenic properties of four primary human immunodeficiency virus type 2 (HIV-2) isolates and two primary HIV-2 biological clones were studied in an in vivo human-to-mouse chimeric model. The cell-associated viral load and the ability to reduce the severity of the induced graft-versus-host disease symptoms, the CD4/CD8 ratio and the level of repopulation of the mouse tissues by the graft, were determined. All HIV-2 strains, irrespective of their in vitro biological phenotype, replicated to high titres and significantly reduced graft-versus-host disease symptoms as well as the CD4/CD8 ratios. Reduction of graft repopulation caused by infection with the respective HIV-2 strains showed that the in vitro replication rate, syncytium-inducing capacity and ability to infect human macrophages did influence the in vivo pathogenic potential whereas broadening of coreceptor usage did not