HIV-1 macrophage tropism is determined at multiple levels of the viral replication cycle.

Abstract

The ability of HIV-1 to infect macrophages is thought to be essential in AIDS pathogenesis. We tested the ability of 19 primary virus isolates to infect monocyte-derived macrophages (MDM) from different donors. Two HIV-1 isolates were able to establish a productive infection in MDM from all donors tested, whereas eight completely lacked this capacity. Next to these isolates with extreme phenotypes, 50% of the primary isolates under study displayed an intermediate phenotype. These intermediate macrophage-tropic isolates established a productive infection in NDM from some but not all donors tested. PCR analysis demonstrated that the capacity to replicate in MDM could be determined at the previously described level of virus entry. However, for intermediate macrophage-tropic isolates replication was abrogated at the level of reverse transcription. Entry of highly macrophage-tropic isolates resulted in efficient completion of the reverse transcription process, whereas entry of intermediate macrophage-tropic isolates did not. Our experiments indicate that primary HIV-1 isolates may differ in their dependency on cellular factors required for reverse transcription in MDM. Differences in susceptibility of MDM for in vitro HIV-1 infection suggest variation in the availability of these cellular factors between MDM from different individuals. (J. Clin. Invest. 1994. 94:1806-1814

Generation of Transmitted/Founder HIV-1 Infectious Molecular Clones and Characterization of Their Replication Capacity in CD4 T Lymphocytes and Monocyte-Derived Macrophages

“…For each donor, the median day 6 LucR values show markedly lower productive MDM infection with T/F Env-IMC-LucR viruses, and across the seven donors the difference between the T/F versus control viruses was statistically significant, as determined by the exact two-tailed Wilcoxon matched-pairs signed-rank test (P ϭ 0.0156). Notably, although considerable variation was observed in virus replication (i.e., level of LucR expression) among the different donor MDM, a phenotype previously reported (7,8,23,29), in each case there remained a difference of 1 to 3 orders of magnitude between T/F and control viruses. This analysis revealed differences in terms of virus infectivity and replication that are similar to those observed studying full-length viruses.…”

“…Nonetheless, these viruses exhibited inefficient cDNA synthesis, infection, and replication in MDM. It is noteworthy that determinants of HIV-1 macrophage tropism may also involve host factors that affect replication at different levels of the virus life cycle subsequent to entry (3,5,29,42). However, since the phenotypes of both the T/F IMCs and control viruses (BaL, YU2, SF162, and JRCSF)-as defined by levels of cDNA synthesis, viral gene expression, and replication-were transferable by expression of their respective Env ectodomains in the isogenic Env-IMC-LucR backbone, it seems unlikely that the "low" macrophage tropism phenotype of T/F viruses is due to interactions between other (non-env) viral determinants and macrophage host restriction factors.…”

Exposure to bacterial products renders macrophages highly susceptible to T-tropic HIV-1.

“…Certain studies reported the inability of T-tropic strains of HIV-1 to efficiently replicate in primary macrophages (42)(43)(44), while others reported that macrophages supported replication of several T-tropic viruses (45,46). Furthermore, a recent study demonstrated that macrophages are a major source of HIV-1 during opportunistic infections in the advanced stage of HIV disease (2).…”

“…In this regard, MDM were infected with HIV and stimulated with microbial products such as LPS, to which macrophages are exposed during conventional or opportunistic infections. To clarify whether different virus strains used in previous studies (42)(43)(44)(45)(46) might have given rise to seemingly conflicting data, we infected MDM with infectious molecular clones that possessed different biological features, including laboratory-adapted T-tropic strain NL4-3, primary T-tropic strain ELI1, dualtropic strain 89.6, and M-tropic strain ADA8.…”

Identification of Shared Populations of Human Immunodeficiency Virus Type 1 Infecting Microglia and Tissue Macrophages outside the Central Nervous System

“…The cellular tropism of human immunodeficiency virus type 1 (HIV-1) is governed at a variety of entry and postentry steps, including the attachment, fusion, and entry of HIV into the cell, reverse transcription, integration, and gene expression (16,31,39). Differences between CD4 lymphocytes, the principal targets of HIV-1 in vivo, and other potential cellular targets for HIV-1, such as macrophages and microglia in the brain, exist at many of these levels, particularly in the expression of CD4 and chemokine coreceptors required for virus entry.…”