Simian immunodeficiency virus SIVrcm, a unique CCR2-tropic virus, selectively depletes memory CD4+ T cells in pigtailed macaques through expanded coreceptor usage in vivo.
Simian immunodeficiency virus SIVrcm, which naturally infects red-capped mangabeys (RCMs), is the only SIV that uses CCR2 as its main coreceptor due to the high frequency of a CCR5 deletion in RCMs. We investigated the dynamics of SIVrcm infection to identify specific pathogenic mechanisms associated with this major difference in SIV biology. Four pigtailed macaques (PTMs) were infected with SIVrcm, and infection was monitored for over 2 years. The dynamics of in vivo SIVrcm replication in PTMs was similar to that of other pathogenic and nonpathogenic lymphotropic SIVs. Plasma viral loads (VLs) peaked at 10(7) to 10(9) SIVrcm RNA copies/ml by day 10 postinoculation (p.i.). A viral set point was established by day 42 p.i. at 10(3) to 10(5) SIVrcm RNA copies/ml and lasted up to day 180 p.i., when plasma VLs decreased below the threshold of detection, with blips of viral replication during the follow-up. Intestinal SIVrcm replication paralleled that of plasma VLs. Up to 80% of the CD4(+) T cells were depleted by day 28 p.i. in the gut. The most significant depletion (>90%) involved memory CD4(+) T cells. Partial CD4(+) T-cell restoration was observed in the intestine at later time points. Effector memory CD4(+) T cells were the least restored. SIVrcm strains isolated from acutely infected PTMs used CCR2 coreceptor, as reported, but expansion of coreceptor usage to CCR4 was also observed. Selective depletion of effector memory CD4(+) T cells is in contrast with predicted in vitro tropism of SIVrcm for macrophages and is probably due to expansion of coreceptor usage. Taken together, these findings emphasize the importance of understanding the selective forces driving viral adaptation to a new host.
Gautam
Rajeev
R
Tulane National Primate Research Center, Covington, LA 70433, USA.
Gaufin
Thaidra
T
Butler
Isolde
I
Gautam
Aarti
A
Barnes
Mary
M
Mandell
Daniel
D
Pattison
Melissa
M
Tatum
Coty
C
Macfarland
Jeanne
J
Monjure
Christopher
C
Marx
Preston A
PA
Pandrea
Ivona
I
Apetrei
Cristian
C
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D006678:HIV / Q000502:physiology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008254:Macaca nemestrina; D008969:Molecular Sequence Data; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology*; D054398:Receptors, CCR4 / Q000235:genetics / Q000276:immunology; D015728:Receptors, HIV / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019562:Viral Load; D053586:Virus Internalization; D014779:Virus Replication
C515354:CCR4 protein, human; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D015728:Receptors, HIV