Paucity of CD4 ⁺ CCR5 ⁺ T Cells May Prevent Transmission of Simian Immunodeficiency Virus in Natural Nonhuman Primate Hosts by Breast-Feeding

Abstract

Simian immunodeficiency virus (SIV) persistence in wild populations of African nonhuman primates (NHPs) may occur through horizontal and vertical transmission. However, the mechanism(s) and timing of the latter type of transmission have not been investigated to date. Here we present the first study of SIV transmissibility by breast-feeding in an African NHP host. Six mandrill dames were infected with plasma containing 300 50% tissue culture infective doses of SIVmnd-1 on the day after delivery. All female mandrills became infected, as demonstrated by both plasma viral loads (VLs) and anti-SIVmnd-1 seroconversion. Neither fever nor lymphadenopathy was observed. At the peak of SIVmnd-1 viral replication (days 7 to 10 postinoculation), plasma VLs were high (8 ؋ 10 6 to 8 ؋ 10 8 RNA copies/ml) and paralleled the high VLs in milk (4.7 ؋ 10 4 to 5.6 ؋ 10 5 RNA/ml). However, at the end of the breast-feeding period, after 6 months of follow-up, no sign of infection was observed for the offspring. Later on, during a 4-year follow-up examination, two of the offspring showed virological evidence of SIVmnd-1 infection. Both animals seroconverted at least 6 months after the interruption of lactation. In conclusion, despite extensive viral replication in mandrill mothers and high levels of free virus in milk, no SIVmnd-1 transmission was detectable at the time of breast-feeding or during the following months. Since we observed a markedly lower expression of CCR5 on the CD4 ؉ T cells of young mandrills and African green monkeys than on those of adults, we propose that low levels of this viral coreceptor on CD4 ؉ T cells may be involved in the lack of breast-feeding transmission in natural hosts of SIVs. Pathogenic human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections of humans and macaques are characterized by the invariable progression to AIDS in a variable time frame (25). The hallmarks of this infection are as follows: (i) continuous depletion of CD4ϩ T cells in peripheral blood (6,23) and at the mucosal sites (7, 34); (ii) continuous viral replication (26,51,68), in which set point viral load (VL) levels are predictive of the progression to AIDS (24, 32, 35-37); and (iii) high levels of immune activation (20, 64), the magnitude of which is also predictive of disease progression (20, 64).In contrast, natural SIV infection of numerous African nonhuman primate (NHP) hosts, including mandrills, African green monkeys (AGMs), and sooty mangabeys (SMs), usually does not progress to AIDS and is characterized by (i) high prevalences in the wild for most species (1,4,29,50,52,57); (ii) an active viral replication, with set point levels similar to or even higher than those reported for pathogenic infection (40,41,44,(47)(48)(49)(59)(60)(61); (iii) a transient depletion of CD4 ϩ T cells in peripheral blood during the primary infection, with a rebound to near preinfection levels during the chronic stage (41,44,47,59); (iv) a significant CD4 ϩ T-cell depletion in the intestine that can be partially restor...

Immunovirological Analyses of Chronically Simian Immunodeficiency Virus SIVmnd-1- and SIVmnd-2-Infected Mandrills (Mandrillus sphinx)

“…Of note, these two models of persistent nonprogressive infection have pathogenic counterparts employing the same viruses, as SIVsmm can be pathogenic in rhesus macaques (RMs) (29,54) and SIVagm is pathogenic in pigtailed macaques (12,17,22; D. Mandell et al, submitted for publication). While these studies of SMs and AGMs have provided a number of important data on the pathophysiology of natural SIV infections (2,4,8,16,18,19,36,38,39,43,56), it can be argued that an approach focusing only on these two models may skew our view of a phenomenon that involves more than 40 different nonhuman primate species. Indeed, differences between SIV infections in SMs and AGMs have even been observed, and species-specific mechanisms employed for controlling disease progression have been identified (1,4,33,67).…”

“…In previous studies, we performed experimental infections of MNDs with the SIVmnd-1 (GB1) and SIVmnd-2 (MND14) reference strains and reported that both viruses show a replication pattern characterized by high peaks of viremia followed by robust levels of virus replication that are associated with transient decreases in peripheral CD4 ϩ T cell counts during the chronic phase of infection (30,31,43,60). Of note, this initial assessment involved only the major T cell populations (i.e., CD4 ϩ and CD8 ϩ T cells) and included a relatively short follow-up period (30,31,43).…”

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

“…This could result from the generation and homing of vaccine-elicited CD4+ T cells to the portal of entry, which in turn mitigates the beneficial effects of the vaccine-elicited humoral immune response (38-40). Indeed, the efficiency of horizontal and vertical SIV transmission in NHP hosts in the absence of vaccination is linked to the availability of susceptible target cells in the mucosa (41)(42)(43). Furthermore, there is strong evidence that genital inflammation reduces the stringency of HIV-1 transmission (25,44,45) and increased target cell availability increases the risk of HIV-1 superinfection (46).…”

Simian immunodeficiency virus types 1 and 2 (SIV mnd 1 and 2) have different pathogenic potentials in rhesus macaques upon experimental cross-species transmission

“…Mandrills 2I and 5A4 and rhesus macaques 93057, 93183A and P9110A were inoculated with 500 ml plasma containing 7.5610 6 RNA copies of SIVmnd-1 (strains 16C and 12A3) (Pandrea et al, 2008a). Mandrills 12D4 and 2H and rhesus macaques 93036, 93183B and 93046A were inoculated with 400 ml plasma containing 2.8610 7 RNA copies of SIVmnd-2 (strain 10I) .…”