The HIV-1 biological phenotype is a practical, binary marker for progression to AIDS, which is independent of decreased CD4+ cell counts and antigenemia. Appearance of SI variants, occurring 2 years before progression to AIDS on the average, is predictive for a significantly increased rate of CD4+ cell decline.

The composition of human immunodeficiency virus type 1 (HIV-1) clonal populations at different stages of infection and in different compartments was analyzed. Biological HIV-1 clones were obtained by primary isolation from patient peripheral blood mononuclear cells under limiting dilution conditions, with either blood donor peripheral blood lymphocytes or monocyte-derived macrophages (MDM) as target cells, and the biological phenotype of the clones was analyzed. In asymptomatic individuals, low frequencies of HIV-1 clones were observed. These clones were non-syncytium inducing and preferentially monocytotropic. In individuals progressing to disease, a 100-fold increase in frequencies of productively HIV-1-infected cells was observed as a result of a selective expansion of nonmonocytotropic clones. In a person progressing to AIDS within 19 months after infection, only syncytium-inducing clones were detected, shifting from MDM-tropic to non-MDMtropic over time. From his virus donor, a patient with wasting syndrome, only syncytium-inducing clones, mostly non-MDM-tropic, were recovered. Parallel clonal analysis of HIV-1 populations in cells present in bronchoalveolar lavage fluid and peripheral blood from an AIDS patient revealed a qualitatively and quantitatively more monocytotropic virus population in the lung compartment than in peripheral blood at the same time point. These findings indicate that monocytotropic HIV-1 clones, probably generated in the tissues, are responsible for the persistence of HIV-1 infection and that progression of HIV-1 infection is associated with a selective increase of T-cell-tropic, nonmonocytotropic HIV-1 variants in peripheral blood.

The third variable (V3) domain has been implicated in determining the human immunodeficiency virus (HIV) phenotype, including fusion capacity and monocytotropism. In a large set of primary H1V type 1 (HIV-1) isolates, V3 sequence analysis revealed that fast-replicating, syncytium-inducing isolates contained V3 sequences with a significantly higher positive charge than those of slow-replicating, non-syncytium-inducing monocytotropic isolates. It appeared that these differences in charge could be attributed to highly variable amino acid residues located on either side of the V3 loop, midway between the cysteine residues and the central GPG motif. In non-syncytium-inducing monocytotropic isolates, these residues were negatively charged or uncharged, whereas in syncytium-inducing nonmonocytotropic isolates, either one or both were positively charged. The substitutions at these positions result in changes in the predicted secondary structure of the V3 loop. Our data suggest that two amino acid residues in the highly variable V3 domain are responsible for phenotype differences and point to conformational differences in V3 loops from phenotypically distinct HIV-1 isolates.

Sequential human immunodeficiency virus (HIV) isolates, recovered from a panel of longitudinally collected peripheral blood mononuclear cells obtained from 20 initially asymptomatic HIV-seropositive homosexual men, were studied for differences in replication rate, syncytium-inducing capacity, and host range. Eleven individuals remained asymptomatic; nine progressed to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) at the time point at which the last HIV isolate was obtained. In 16 individuals, only non-syncytium-inducing (NSI) isolates, with a host range restricted to mononuclear cells, were observed. From four individuals, high-replicating, syncytium-inducing (SI) isolates that could be transmitted to the H9, RC2A, and U937 cell lines were recovered. From two of these four individuals, SI isolates were obtained throughout the observation period. In the two others, a transition from NSI to SI HIV isolates was observed during the period of study. Three of these four individuals developed ARC or AIDS 9 to 15 months after the first isolation of an SI isolate. With the exception of the two individuals in whom a transition from NSI to SI isolates was observed, within a given individual the replication rate of sequential HIV isolates was constant. A significant correlation was found between the mean replication rate of isolates obtained from an individual and the rate of CD4+ cell decrease observed in this individual. In individuals with low-replicating HIV isolates, no significant CD4+ cell loss was observed. In contrast, recovery of high-replicating isolates, in particular when these were SI isolates, was associated with rapid decline of CD4+ cell numbers and development of ARC or AIDS. These findings indicate that variability in the biological properties of HIV isolates is one of the factors influencing the course of HIV infection.

Human immunodeficiency virus (HIV), the causative agent of AIDS, infects human lymphocytes and monocytes. An interaction between the viral envelope gp 120 and CD4 protein is required to initiate an infectious cycle. HIV infection in vitro induces syncytium formation by cell-to-cell fusion; this aspect of viral cytopathogenicity is even more dependent on gp120-CD4 interactions. That gp120 is extremely heavily glycosylated (31-36 N-linked glycans per molecule), suggests involvement of N-linked glycans in the gp120-CD4 interaction. We therefore investigated the effects of castanospermine, 1-deoxynojirimycin (dNM) and 1-deoxymannojirimycin (dMM), three trimming glycosidase inhibitors which perturb N-linked glycan structure, on induction of the formation of syncytium between HIV-infected and CD4-expressing cells. The glucosidase inhibitors castanospermine and dNM, but not the mannosidase inhibitor dMM, inhibited syncytium formation and interfered with infectivity. The potential of glucosidase inhibitors as anti-HIV therapeutic agents deserves further investigation, especially because dNM and related compounds show little toxicity in vitro and in vivo.