Up‐regulation of β‐chemokines and down‐modulation of CCR5 co‐receptors inhibit simian immunodeficiency virus transmission in non‐human primates

) and vaccinated, unprotected (n ‫؍‬ 11) monkeys by measuring beta-chemokine mRNA levels and protein expression, the frequency of CD8 ؉ T cells expressing beta-chemokines, and the extent of CD8 ؉ -T-cell proliferation. Tissues from uninfected (n ‫؍‬ 3) and unvaccinated, SIVmac239-infected (n ‫؍‬ 9) monkeys served as controls. Axillary and genital lymph nodes from unvaccinated and vaccinated, unprotected monkeys had significantly higher beta-chemokine mRNA expression levels and increased numbers of beta-chemokine-positive cells than did vaccinated, protected animals. Furthermore, the lymph nodes of vaccinated, unprotected monkeys had significantly higher numbers of beta-chemokine ؉ CD8 ؉ T cells than did vaccinated, protected monkeys. Lymph nodes from vaccinated, unprotected animals also had significantly more CD8 ؉ -T-cell proliferation and marked lymph node hyperplasia than the lymph nodes of vaccinated, protected monkeys. Thus, higher levels of virus replication were associated with increased beta-chemokine secretion and there is no evidence that betachemokines contributed to the SHIV89.6-mediated control of viral replication after intravaginal challenge with SIVmac239.

Section: Discussioncontrasting

confidence: 88%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

High Beta-Chemokine Expression Levels in Lymphoid Tissues of Simian/Human Immunodeficiency Virus 89.6-Vaccinated Rhesus Macaques Are Associated with Uncontrolled Replication of Simian Immunodeficiency Virus Challenge Inoculum

LaFranco-Scheuch

Abel

Makori

et al. 2004

“…The antibodies for these flow cytometric determinations have been used repeatedly by our laboratories and the laboratories of others to identify CD4 and CCR5 on the surface of rhesus monkey cells with good sensitivity (2,34,35,48,49,53,55,66). For the present experiments, we used appropriate CD4/CCR5-positive and -negative controls to establish gating and sensitivity.…”

Section: Cd4mentioning

confidence: 99%

Mechanisms for Adaptation of Simian Immunodeficiency Virus to Replication in Alveolar Macrophages

Mori

Rosenzweig

Desrosiers

2000

In contrast to the simian immunodeficiency virus SIVmac239, which replicates poorly in rhesus monkey alveolar macrophages, a variant with nine amino acid changes in envelope (SIVmac239/316E) replicates efficiently and to high titer in these same cells. We examined levels of viral DNA, RNA, antigen, and infectious virus to identify the nature of the block to SIVmac239 replication in these cells. Low levels of viral antigen (0.1 to 1.0 ng of p27 per ml) and infectious virus (100 to 1,000 infectious units per ml) were produced in the supernatant 1 to 4 days after SIVmac239 infection, but these levels did not increase subsequently. SIVmac239 DNA was synthesized in these macrophage cultures during the initial 24 h after infection, but the levels did not increase subsequently. Quantitation of the numbers of infectious cells in cultures over time and the results of experiments in which cells were reexposed to SIVmac239 after the initial exposure indicated that only a small proportion of cells were susceptible to SIVmac239 infection in these alveolar macrophage cultures and that the vast majority (>95%) of cells were refractory to SIVmac239 infection. In contrast to the results with SIVmac239, the levels of viral antigen, infectious virus, and viral DNA increased exponentially 2 to 7 days after infection by SIVmac239/316E, reaching levels greater than 100 ng of p27 per ml and 100,000 infectious units per ml. Since SIVmac239/316E has previously been described as a virus capable of infecting cells in a relatively CD4-independent fashion, we examined the levels of CD4 expression on the surface of fresh and cultured alveolar macrophages from rhesus monkeys. The levels of CD4 expression were extremely low, below the limit of detection by flow cytometry, on greater than 99% of the macrophages. CCR5؉ cells were profoundly depleted only from alveolar macrophage cultures infected with SIVmac239/316E. High concentrations of an antibody to CD4 delayed but did not block replication of SIVmac239/316E. The results suggest that the adaptation of SIVmac316 to efficient replication in alveolar macrophages results from its ability to infect these cells in a CD4-independent fashion or in a CD4-dependent fashion even at extremely low levels of surface CD4 expression. Since resident macrophages in brains and lungs of humans also express little or no CD4, our findings predict the presence of human immunodeficiency virus type 1 that is relatively CD4 independent in the lung and brain compartments of infected people.

“…This mechanism is independent of HIV or SIV priming and thus constitutes noncognate immunity to these viruses. The mechanism of protection involves the three CC chemokines (CCL3, CCL4, and CCL5) which are elicited in vitro and in vivo by the stimulation of human or simian CD4 ϩ T cells and dendritic cells with HSP70 (21,39). These chemokines inhibit preentry HIV-1 binding to CCR5 by the R5 strains of HIV-1 and by most SIV strains (9,24); CCL3 may also inhibit postentry HIV-1 (3).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Infection of Human CD4 ⁺ T Cells by Microbial HSP70 and the Peptide Epitope 407-426

Babaahmady

Oehlmann

Singh

et al. 2007

Targeting the cognate human immunodeficiency virus type 1 (HIV-1) antigen is the classical way of preventing HIV-1 infection, but this approach has encountered serious problems in eliciting effective cytotoxic T lymphocytes (CTL) and neutralizing antibodies. Both CTL and neutralizing antibodies are subject to viral escape, and HIV-1 mutation may occur in the acute (30), as well as the chronic, phase of infection (4,12,15). Indeed, HIV-1 sequences found in a population may represent largely CTL escape variants restricted by the most prevalent HLA alleles in that population (29). Alternative preventive strategies such as the use of host antigens may have to be considered. Among a large, nonrandom selection of host proteins, HSP70 was found in the virion membrane of HIV-1; the amount was similar to that of Pol protein, and HSP70 functions as a chaperone during intracellular transport (17). HSP70 mRNA is upregulated in CD4 ϩ T cells infected with HIV-1 (35), and the expression of HSP70 is significantly increased in lymphocytes from HIV-1-infected subjects (1). HSP70 elicits innate immune responses by generating chemokines and cytokines (23, 27, 38), which exert robust adjuvanticity in nonhuman primates (5). Furthermore, alloimmune responses can be enhanced by stimulating the CD40-CD40L costimulatory pathway (13) and the alternative CD40-HSP70 pathway may function in a similar way by upregulating CD40, CD80/86, HLA-II, and tumor necrosis factor alpha (TNF-␣) (38, 39). Recently, we and others have demonstrated that HSP70 binds directly to CCR5 expressed on the surfaces of human CD4 ϩ T cells and dendritic cells (11,41).The aims of the present investigations were to explore and characterize any inhibitory effect of microbial HSP70 on HIV-1. An examination of the effect of HSP70 on HIV infectivity revealed a dose-dependent inhibition of HIV-1 infection of activated CD4 ϩ T cells. The inhibitory function of HSP70 was progressively localized, first to the C-terminal fragment (the peptide comprising amino acids [aa] 359 to 609 [p359-609]), then to the peptide binding domain (p359-494), and finally to the 20-mer peptide epitope (aa 407 to 426). The kinetics of the HIV-1-inhibitory effects of the HSP70 peptides over 24 h were comparable for HSP70, p359-609, and p359-494, though the duration of inhibition varied among the HSP70 fragments. We then explored any complementary inhibitory effect on HIV-1 by adding anti-CCR5 monoclonal or polyclonal antibodies to HSP70. Whereas HSP70 alone inhibited the R5 strains of HIV-1 in a dose-dependent way by up to a mean (Ϯ the standard error of the mean [SEM]) of 72.8% (Ϯ14.8%) and monoclonal antibody (mAb) to CCR5 inhibited HIV-1 up to 93.5% (Ϯ3.9%), combining HSP70 with mAb to CCR5 enhanced the level of inhibition to 99.7% (Ϯ0.9%). MATERIALS AND METHODSPreparation of HSP70, its C-terminal (aa 359 to 609) and N-terminal (aa 1 to 358) fragments, and the peptide binding domain (aa 359 to 494). The recombinant Mycobacterium tuberculosis HSP70, p359-609, p1-358, and p359-494 were prepared fr...