Comparing the Ex Vivo Fitness of CCR5-Tropic Human Immunodeficiency Virus Type 1 Isolates of Subtypes B and C

Abstract

Continual human immunodeficiency virus type 1 (HIV-1) evolution and expansion within the human population have led to unequal distribution of HIV-1 group M subtypes. In particular, recent outgrowth of subtype C in southern Africa, India, and China has fueled speculation that subtype C isolates may be more fit in vivo. In this study, nine subtype B and six subtype C HIV-1 isolates were added to peripheral blood mononuclear cell cultures for a complete pairwise competition experiment. All subtype C HIV-1 isolates were less fit than subtype B isolates (P < 0.0001), but intrasubtype variations in HIV-1 fitness were not significant. Increased fitness of subtype B over subtype C was also observed in primary CD4؉ T cells and macrophages from different human donors but not in skin-derived human Langerhans cells. Detailed analysis of the retroviral life cycle during several B and C virus competitions indicated that the efficiency of host cell entry may have a significant impact on relative fitness. Furthermore, phyletic analyses of fitness differences suggested that, for a recombined subtype B/C HIV-1 isolate, higher fitness mapped to the subtype B env gene rather than the subtype C gag and pol genes. These results suggest that subtype B and C HIV-1 may be transmitted with equal efficiency (Langerhans cell data) but that subtype C isolates may be less fit following initial infection (T-cell and macrophage data) and may lead to slower disease progression.

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

“…This finding is not consistent with the hypothesis that reduced replication fitness in cell culture correlates with reduced transmission efficiency. Of note is that some studies suggested that replication in dendritic cells may be a better predictor of transmission efficiency (50); no differences between the replication of subtype B and C isolates were observed in dendritic cells, consistent with this theory (11). The authors of that study argued that the reduced replication fitness in PBMCs correlates with reduced pathogenicity rather than transmission efficiency (see below).…”

“…However, another study demonstrated that subtype C, which is the most common subtype globally, actually has reduced replication fitness compared to subtype B in PBMCs (6,11). This finding is not consistent with the hypothesis that reduced replication fitness in cell culture correlates with reduced transmission efficiency.…”

“…A whole-virus, multiple-cycle growth competition assay in primary human PBMCs in which the relative proportion of test and reference viruses is measured using an HTA has been used to study the effects of env on fitness and disease progression and to evaluate the relative fitnesses of different subtypes of HIV-1 (6,11,140,164). Because this growth competition assay utilizes an intact viral isolate and primary human PBMCs, it likely provides the closest approximation to HIV-1 replication fitness in patients compared to other currently available assays, but its labor-intensive nature limits its use for large-scale studies correlating fitness with clinical outcomes.…”

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

“…1D). In addition to the HIV p24 staining and transmission electron microscopy (TEM), we have recently reported that HIV transcripts can be detected and quantified within crawl-out LCs, further confirming productive infection of these cells (40).…”

“…Whether CCR5 influences initial infection at the level of the LCs, at the level of the epithelial cell (43,44), at early replication steps in lymphoid tissue, or at multiple sites, however, is less clear. The former theories can be described as primary gatekeeper models, whereas the latter process represents a viral fitness model (40).…”