Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4(+) T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4(+) T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-alpha in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.

HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.

Here we present the first molecular characterization of the defect associated with an avian sarcoma and leukosis virus (ASLV) receptor resistance allele, tvb r . We show that resistance to infection by subgroups B, D, and E ASLV is explained by the presence of a single base pair mutation that distinguishes this allele from tvb s1 , an allele which encodes a receptor for all three viral subgroups. This mutation generates an in-frame stop codon that is predicted to lead to the production of a severely truncated protein.Functionally distinct alleles of the autosomal tva, tvb, and tvc loci that encode avian sarcoma and leukosis virus (ASLV) receptors have been defined for chickens (reviewed in references 12 and 22). Two classes of tva and tvc alleles are associated with either susceptibility (tva s and tvc s ) or resistance (tva r and tvc r ) to infection by subgroup A ASLV or subgroup C ASLV, respectively. The tvb locus is more complex since two chicken alleles of tvb that encode distinct ASLV receptors have been defined: tvb s1 for viral subgroups B, D, and E and tvb s3 for subgroups B and D (1, 2, 9, 20). In addition, there is another type of allele (tvb r ) that cannot support entry by any of these ASLV subgroups (12). For each ASLV receptor gene, alleles that confer susceptibility to viral infection are dominant over those associated with resistance. Therefore, the only lines of chickens that are resistant to infection by subgroups A through D ASLVs are those that are homozygous for the resistance alleles of the cognate receptor gene. Resistance to subgroup E viral infection is more complicated because of the existence of endogenous ASLV elements in the chicken germ line which encode subgroup E ASLV-specific envelope (Env) proteins that interfere with the function of the TVB S1 receptor (1, 7). The recessive nature of the tva r , tvb r , and tvc r alleles rules out the possibility that their products interfere, in a dominantnegative manner, with those encoded by the corresponding susceptibility alleles. Instead, the defect(s) associated with these resistance alleles may be due either to their lack of expression or to the existence of specific amino acid substitutions in the corresponding proteins that abolish viral receptor function.The tva s allele encodes a low-density lipoprotein (LDL) receptor-related protein that is a cellular receptor for ASLV subgroup A (5, 6, 26). The TVA protein contains an approximately 40-amino-acid long LDL-A module that harbors the major viral interaction determinants (16,17,27,28). The molecular defect that is associated with the tva r allele has not yet been defined, but a preliminary characterization of this allele has documented no obviously debilitating defects within the LDL-A domain (5).TVB is a tumor necrosis factor receptor (TNFR)-related death receptor that is most similar to the mammalian TNFrelated apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5 (1). TVB contains three extracellular cysteine-rich domains and a cytoplasmic death domain which can activate apoptosi...

The chicken TVB(S1) protein serves as the cellular receptor for the cytopathic subgroups B and D avian sarcoma and leukosis viruses (ASLVs) as well as for the non-cytopathic subgroup E ASLV. Previous studies had mapped the subgroup B viral interaction determinants to a region that was located between residues 32 and 46 of TVB(S1) [J. Virol. 76 (2002) 5404]. To gain a greater insight into ASLV Env-receptor interactions and the possible role of these interactions in viral cytopathic effects, we employed a homolog-scanning mutagenesis approach to identify amino acid residues important for subgroup E viral receptor function by exchanging amino acid residues between TVB(S1) and its human homolog, DR5. These studies identified residues Tyr-67, Asn-72, and Asp-73 of TVB(S1) as important subgroup E viral interaction determinants. Intriguingly, these three residues are conserved between TVB(S1) and DR5, demonstrating that the human protein contains critical subgroup E viral interaction determinants, but in this context, they cannot support viral entry. These data confirm that the molecular determinants of the TVB receptor required for subgroup E viral entry are completely distinct from those used by subgroup B viruses.