Definition of the Stage of Host Cell Genetic Restriction of Replication of Human Immunodeficiency Virus Type 1 in Monocytes and Monocyte-Derived Macrophages by Using Twins

Abstract

Using identical (ID) twins, we have previously demonstrated that host cell genes exert a significant impact on productive human immunodeficiency virus (HIV) infection of monocytes and macrophages (J. Chang et al., J. Virol. 70:7792–7803, 1996). Therefore, the stage in the replication cycle at which these host genetic influences act was investigated in a study using 8 pairs of ID twins and 10 pairs of sex- and age-matched unrelated donors (URDs). In the first phase of the study, blood monocytes and monocyte-derived macrophages (MDM) of ID twins and URDs were infected with 15 HIV type 1 strains. Four well-characterized primary isolates and HIV-BaL were then examined in more detail. The host cell genetic effect in MDM was exerted predominantly prior to complete reverse transcription, as the HIV DNA level and p24 antigen levels were concordant (r = 0.91, P = 0.0001) and similar between the pairs of ID twin pairs (r = 0.96,P = 0.0001) but discordant between URD pairs (r = 0.11, P = 0.3) in both phases of the study. To further examine genetic influence on viral entry, we examined the proportion of CCR5 membrane expression on MDM. As expected, there was wide variability in proportion of MDM expressing CCR5 among URDs (r = 0.58, P = 0.2); however, this variability was significantly reduced between ID twin pairs (r = 0.81, P = 0.01). Differences in viral entry did not necessarily correlate with CCR5 expression, and only very low levels of CCR5 expression restricted HIV entry and production. In summary, the host cell genetic effect on HIV replication in macrophages appears to be exerted predominantly pre-reverse transcription. Although CCR5 was necessary for infection, other unidentified host genes are likely to limit productive infection.

Persistent CCR5 Utilization and Enhanced Macrophage Tropism by Primary Blood Human Immunodeficiency Virus Type 1 Isolates from Advanced Stages of Disease and Comparison to Tissue-Derived Isolates

“…In monocytes, where such correlation was not as high as in MDM, restriction to replication occurred both before and after RT. These results confirmed our previous report with blood isolates, which showed that this restriction to viral entry (or uncoating) may be due predominantly to viral factors with some strains or to an interaction between viral and host factors with others (49).…”

“…Viral entry is the primary determinant of tropism for macrophages, T lymphocytes, and T-cell lines and also the major bottleneck for productivity of infection in MDM (49). Therefore, the assessment of coreceptor usage of primary isolates from the different stages of infection and disease is essential to understanding the relationship between viral tropism, productivity, and disease progression.…”

“…An evolving increase in HIV genomic diversity, especially in the envelope gene, underlies all of the changes in the biologic characteristics of HIV, including altered cytopathic ability, cell tropism, coreceptor usage, and immune system evasion during disease progression (5,12,14,35,74,77). The drivers of this genomic diversity and the consequent biologic changes must be the interactions between HIV-1 and the host genetic factors, especially those controlling the relevant proteins interacting during viral replication within the predominant infected cell types in blood and tissues (19,45,49).…”

The influence of cytokines, chemokines and their receptors on HIV‐1 replication in monocytes and macrophages

“…However, genetic factors other than CCR5 expression may also influence the outcome of HIV-1 infection and replication in cells of macrophage lineage. The kinetics of HIV-1 replication in macrophages obtained from identical twin pairs was more similar to each other than in those obtained from sex-and age-matched unrelated donors [93]. In these carefully matched studies, the level of surface expression of CCR5 did not exactly correlate with viral entry.…”

“…As a result of a pre-reverse transcription block, placental macrophages are not HIV-1 and macrophages HIV-1 and macrophages 43 43 susceptible to HIV-1 infection with over 20 primary M-tropic isolates. Similarly, the ability of low-replicating primary M-tropic isolates derived from patients at an early asymptomatic stage of disease to replicate in MDM is also restricted before reverse transcription, possibly at the level of viral entry or uncoating [35,93]. Whilst the block to HIV-1 infection in monocytes occurs prior to RT and integration [19] and is predominantly at the level of fusion and entry [35,93], the cellular environment including the constitutive expression of the cellular transcription factor, NF-B also contributes to the reduced susceptibility to infection in monocytes [94].…”