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Preservation of memory CD4(+) T lymphocytes in breast milk of lactating rhesus monkeys during acute simian immunodeficiency virus infection.

ABSTRACT: Acute human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection is associated with a massive depletion of memory CD4(+) T lymphocytes in the gastrointestinal tract. To define the dynamics of the CD4(+) T lymphocyte subpopulations in breast milk during acute HIV or SIV infection, lymphocyte populations were monitored in blood and milk of 4 Mamu-A*01(+) rhesus monkeys after SIVmac251 inoculation. Strikingly, although the CD4(+) T lymphocytes in blood were depleted during the peak of viremia, the milk CD4(+) T lymphocyte counts remained unchanged, despite active virus replication in the breast milk compartment. Moreover, CD4(+) memory T lymphocytes were preserved in breast milk during acute infection. CD4(+) T lymphocytes in breast milk and other mucosal compartments of uninfected monkeys were similar in their memory phenotype, activation status, and chemokine (C-C motif) receptor 5 expression. Interestingly, the number and proportion of effector CD8(+) T lymphocytes in milk were increased during acute SIV infection, suggesting effective control of virus-mediated CD4(+) T lymphocyte destruction in the breast milk compartment.

SUBMITTER: Permar SR

PROVIDER: S-EPMC2940712 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Preservation of memory CD4(+) T lymphocytes in breast milk of lactating rhesus monkeys during acute simian immunodeficiency virus infection.

Permar Sallie R SR Kang Helen H HH Carville Angela A Wilks Andrew B AB Mansfield Keith G KG Rao Srinivas S SS Letvin Norman L NL

The Journal of infectious diseases 20100101 2

Acute human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection is associated with a massive depletion of memory CD4(+) T lymphocytes in the gastrointestinal tract. To define the dynamics of the CD4(+) T lymphocyte subpopulations in breast milk during acute HIV or SIV infection, lymphocyte populations were monitored in blood and milk of 4 Mamu-A*01(+) rhesus monkeys after SIVmac251 inoculation. Strikingly, although the CD4(+) T lymphocytes in blood were depleted during ...[more]

PMID: 20001855

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Project description:The importance of the vpr gene for simian immunodeficiency virus (SIV) replication, persistence, and disease progression was examined by using the infectious pathogenic molecular clone called SIVmac239. The ATG start codon of the vpr gene was converted to TTG by site-specific mutagenesis. The constructed Vpr- mutant virus is identical with the parental SIVmac239/nef-stop virus with the exception of this one nucleotide. These viruses replicated with similar kinetics and to similar extents in rhesus monkey lymphocyte cultures and in the human CEMX174 cell line. Five rhesus monkeys were inoculated with the Vpr- variant of SIVmac239/nef-stop, and two monkeys received SIVmac239/nef-stop as controls. Both controls showed reversion of the TAA stop signal in nef by 2 weeks postinfection, as has been observed previously. Reversion of the TAA stop codon in nef also occurred in the five monkeys that received the Vpr- variant, but reversion was delayed on average to about 4 weeks. Thus, the mutation in vpr appeared to delay the rapidity with which reversion occurred in the nef gene. Reversion of the TTG sequence in vpr to ATG was observed in three of the five test animals. Reversion in vpr was first observed in these three animals 4 to 8 weeks postinfection. No vpr revertants were found over the entire 66 weeks of observation in the other two test animals that received the vpr mutant. Antibodies to vpr developed in those three animals in which reversion of vpr was documented, but antibodies to vpr were not observed in the two animals in which reversion of vpr was not detected. Antibody responses to gag and to whole virus antigens were of similar strength in all seven animals. Both control animals and two of the test animals in which vpr reverted maintained high virus loads and developed progressive disease. Low virus burden and no disease have been observed in the two animals in which vpr did not revert and in the one animal in which vpr reversion was first detected only at 8 weeks. The reversion of vpr in three of the five test animals indicates that there is significant selective pressure for functional forms of vpr in vivo. Furthermore, the results suggest that both vpr and nef are important for maximal SIV replication and persistence in vivo and for disease progression.

Project description:Rhesus macaques are used to model human immunodeficiency virus type 1 (HIV-1) infections, but they are not natural hosts of HIV-1 or any simian immunodeficiency virus (SIV). Rather, they became infected with SIV through cross-species transfer from sooty mangabeys in captivity. It has been shown that HIV-1 utilizes rhesus CD4 less efficiently than human CD4. However, the relative ability of SIV envelope glycoproteins to bind or utilize these CD4 orthologs has not been reported. Here we show that several SIV isolates, including SIVmac239, are more efficiently neutralized by human CD4-Ig (huCD4-Ig) than by the same molecule bearing rhesus CD4 domains 1 and 2 (rhCD4-Ig). An I39N mutation in CD4 domain 1, present in human and sooty mangabey CD4 orthologs, largely restored rhCD4-Ig neutralization of SIVmac239 and other SIV isolates. We further observed that SIVmac316, a derivative of SIVmac239, bound to and was neutralized by huCD4-Ig and rhCD4-Ig with nearly identical efficiencies. Introduction of two SIVmac316 CD4-binding site residues (G382R and H442Y) into the SIVmac239 envelope glycoprotein (Env) markedly increased its neutralization sensitivity to rhesus CD4-Ig without altering neutralization by human CD4-Ig, SIV neutralizing antibodies, or sera from SIV-infected macaques. These changes also allowed SIVmac239 Env to bind rhCD4-Ig more efficiently than huCD4-Ig. The variant with G382R and H442Y (G382R/H442Y variant) also infected cells expressing rhesus CD4 with markedly greater efficiency than did unaltered SIVmac239 Env. We propose that infections of rhesus macaques with SIVmac239 G382R/H442Y might better model some aspects of human infections.IMPORTANCE Rhesus macaque infection with simian immunodeficiency virus (SIV) has served as an important model of human HIV-1 infection. However, differences between this model and the human case have complicated the development of vaccines and therapies. Here we report the surprising observation that SIVmac239, a commonly used model virus, more efficiently utilizes human CD4 than the CD4 of rhesus macaques, whereas the closely related virus SIVmac316 uses both CD4 orthologs equally well. We used this insight to generate a form of SIVmac239 envelope glycoprotein (Env) that utilized rhesus CD4 more efficiently, while retaining its resistance to antibodies and sera from infected macaques. This Env can be used to make the rhesus model more similar in some ways to human infection, for example by facilitating infection of cells with low levels of CD4. This property may be especially important to efforts to eradicate latently infected cells.

Dataset Information

Preservation of memory CD4(+) T lymphocytes in breast milk of lactating rhesus monkeys during acute simian immunodeficiency virus infection.

Publications

Preservation of memory CD4(+) T lymphocytes in breast milk of lactating rhesus monkeys during acute simian immunodeficiency virus infection.

Similar Datasets

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