Abstract
Analysis of rhesus macaques infected with a vpx deletion mutant virus of simian immunodeficiency virus mac239 (SIVΔvpx) demonstrates that Vpx is essential for efficient monocyte/macrophage infection in vivo but is not necessary for development of AIDS. To compare myeloid-lineage cell infection in monkeys infected with SIVΔvpx compared to SIVmac239, we analyzed lymphoid and gastrointestinal tissues from SIVΔvpx-infected rhesus (n = 5), SIVmac239-infected rhesus with SIV encephalitis (7 SIV239E), those without encephalitis (4 SIV239noE), and other SIV mutant viruses with low viral loads (4 SIVΔnef, 2 SIVΔ3). SIV+ macrophages and the percentage of total SIV+ cells that were macrophages in spleen and lymph nodes were significantly lower in rhesus infected with SIVΔvpx (2.2%) compared to those infected with SIV239E (22.7%), SIV239noE (8.2%), and SIV mutant viruses (10.1%). In colon, SIVΔvpx monkeys had fewer SIV+ cells, no SIV+ macrophages, and lower percentage of SIV+ cells that were macrophages than the other 3 groups. Only 2 SIVΔvpx monkeys exhibited detectable virus in the colon. We demonstrate that Vpx is essential for efficient macrophage infection in vivo and that simian AIDS and death can occur in the absence of detectable macrophage infection.
Highlights
While all lineages of HIV and SIV encode an accessory protein termed viral protein R (Vpr), only some, the HIV-2, SIVSM, and SIVMAC lineages, encode viral protein X (Vpx) [1,2,3]
All 5 SIVDvpx-infected rhesus developed AIDS with AIDSdefining lesions including opportunistic infections (Table 2), while none developed multinucleated giant cell disease (GCD) or SIV giant cell encephalitis (SIVE), both disease manifestations of lentiviral infection characterized by histologically distinctive infected macrophages [23,24,25]
SIVDvpxinfected animals had prolonged survival, they did eventually succumb to AIDS with CD4 decline despite the fact that there was little to no infection of macrophages [20]
Summary
While all lineages of HIV and SIV encode an accessory protein termed viral protein R (Vpr), only some, the HIV-2, SIVSM, and SIVMAC lineages, encode viral protein X (Vpx) [1,2,3]. Despite the recognition that Vpx and Vpr have distinct functions [5], they both have been reported to play a role in viral replication in macrophages and dendritic cells [2,6,7,8,9,10,11]. While Vpr may enhance viral replication in myeloid-lineage cells in vitro [6], the effect of Vpx on replication in myeloid cells is even more dramatic [6,7]. SAMHD1 would otherwise inhibit viral infection of myeloid and dendritic cells by depleting deoxynucleotide triphosphates (dNTPs) needed by the lentivirus to complete reverse transcription [9]. Through mechanisms still under examination, SAMHD1 is able to restrict replication of virus transmitted by cell-to-cell contact to monocyte-derived dendritic cells (MDDCs) [17]
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