Differential Tropism and Chemokine Receptor Expression of Human Immunodeficiency Virus Type 1 in Neonatal Monocytes, Monocyte-Derived Macrophages, and Placental Macrophages

Abstract

Laboratory-adapted (LA) macrophage-tropic (M-tropic) human immunodeficiency virus type 1 (HIV-1) isolates (e.g., HIV-1Ba-L) and low-passage primary (PR) isolates differed markedly in tropism for syngeneic neonatal monocytes, monocyte-derived macrophages (MDMs), and placental macrophages (PMs). Newly adherent neonatal monocytes and cultured PMs were highly refractory to infection with PR HIV-1 isolates yet were permissive for LA M-tropic isolates. Day 4 MDMs were also permissive for LA M-tropic isolates and additionally, were permissive for over half the PR isolates tested. Qualitative differences in PR HIV-1 infection of monocytes/MDMs could not be correlated with CD4 levels alone, and in all three cell types the block to PR HIV-1 strain replication preceded reverse transcription. Neonatal monocyte susceptibility to PR HIV-1 strains correlated with increasing CCR-5 expression during maturation. CCR-5 could not be detected on newly adherent (day 1) neonatal monocytes, in contrast to adult monocytes (H. Naif et al., J. Virol. 72:830–836, 1998), but was readily detectable after 4 to 7 days of culture. However, moderate CCR-5 mRNA levels were present in day 1 neonatal monocytes and remained constant during monocyte maturation. CCR-5 was not detectable on the surface of PMs, yet the receptor was present within permeabilized cells. Notably, two brain-derived PR HIV-1 isolates from a single patient, differing in their V3 loops, were discordant in their abilities to infect neonatal monocytes/MDMs and PMs, yet both isolates could infect newly adherent adult monocytes. Together these data strongly suggest that LA HIV-1 isolates are able to infect neonatal monocytes at earlier stages of maturation and lower-level expression of CCR-5 than PR isolates. The differences between neonatal and adult monocytes in susceptibility to PR isolates may also be related to the level of CCR-5 expression.

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

“…CCR3 receptor expression is not detected on adult monocytes, concordant with lack of CCR3 mRNA [38]. Both adult [48][49][50] and neonatal [46] monocytes express CD4.…”

“…Whilst CCR5 transcripts are readily detected in freshly isolated monocytes, CCR5 surface expression is not detected on these cells [38,44,45]. Following 24 h in culture, surface CCR5 is observed on monocytes from adult but not neonatal donors [38,46]. The surface expression of CXCR4 and CCR2b is high on freshly isolated monocytes [38,47].…”

Specific CD4 down-modulating compounds with potent anti-HIV activity

“…CCR5-transfected HeLa-CD4 cells could be infected by R5 HIV-1 isolates even if those cells had small amounts of CD4 [61], and the susceptibility of maturing monocytes to HIV-1 infection correlated with CCR5 expression [65]. Furthermore, the differences between neonatal and adult monocytes in susceptibility to primary clinical isolates may be related to the level of CCR5 expression [66]. However, the CD4 and CCR5 concentration requirements for efficient infections by R5 HIV-1 are interdependent: cells with a large amount of CD4 required only a trace amount of CCR5 for maximal susceptibility to infection by diverse isolates of R5 HIV-1, whereas cells with a low amount of CD4 required a much larger amount of CCR5 for infection [63].…”

Restricted HIV-1 replication in placental macrophages is caused by inefficient viral transcription

“…Despite this susceptibility, our laboratory and others [4 -8] have demonstrated that HIV-1 production by PM is significantly lower than that observed in MDM. PM express lower levels of the CD4, CXCR4, and CCR5 receptors than do MDM [9,10]. LPS-stimulated PM produce lower levels of proinflammatory cytokines than do LPS-stimulated MDM, but there is no correlation of cytokine secretion with HIV-1 infection [8].…”