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Vaccination-induced noncytolytic effects in the acute phase of SHIV infection.

ABSTRACT: Many studies have shown that vaccines inducing CD8+ T cell responses can reduce viral loads and preserve CD4+ T cell numbers in monkey models of HIV infection. The mechanism of viral control by the vaccine-induced CD8+ T cells is usually assumed to be cytolysis of infected cells. However, in addition to cytolysis of infected cells, CD8+ T cells secrete a range of soluble factors that suppress viral replication. We have studied the dynamics of virus and CD4+ T cells in a successful vaccination-challenge model of SHIV infection. We find that better viral control in the acute phase of infection is associated with slower decay of peak viral load. Comparing viral and CD4+ T cell dynamics in acute infection, we find that a cytolytic mode of viral control with direct killing of infected cells is inconsistent with the observed trends. On the other hand, comparison of the predicted effects of noncytolytic CD8+ effector function with the experimental data shows that non-cytolytic control provides a better explanation of the experimental results. Our analysis suggests that vaccine-induced CD8+ T cells control SHIV infection by non-cytolytic means.

SUBMITTER: Petravic J

PROVIDER: S-EPMC2994900 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Vaccination-induced noncytolytic effects in the acute phase of SHIV infection.

Petravic Janka J Davenport Miles P MP

PloS one 20101130 11

Many studies have shown that vaccines inducing CD8+ T cell responses can reduce viral loads and preserve CD4+ T cell numbers in monkey models of HIV infection. The mechanism of viral control by the vaccine-induced CD8+ T cells is usually assumed to be cytolysis of infected cells. However, in addition to cytolysis of infected cells, CD8+ T cells secrete a range of soluble factors that suppress viral replication. We have studied the dynamics of virus and CD4+ T cells in a successful vaccination-ch ...[more]

PMID: 21152101

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Project description:BackgroundImmunosurveillance of the central nervous system (CNS) is vital to resolve infection and injury. However, immune activation within the CNS in the setting of chronic viral infections, such as HIV-1, is strongly linked to progressive neurodegeneration and cognitive decline. Establishment of HIV-1 in the CNS early following infection underscores the need to delineate features of acute CNS immune activation, as these early inflammatory events may mediate neurodegenerative processes. Here, we focused on elucidating molecular programs of neuroinflammation in brain regions based on vulnerability to neuroAIDS and/or neurocognitive decline. To this end, we assessed transcriptional profiles within the subcortical white matter of the pre-frontal cortex (PFCw), as well as synapse dense regions from hippocampus, superior temporal cortex, and caudate nucleus, in rhesus macaques following infection with Simian/Human Immunodeficiency Virus (SHIV.C.CH505).MethodsWe performed RNA extraction and sequenced RNA isolated from 3 mm brain punches. Viral RNA was quantified in the brain and cerebrospinal fluid by RT-qPCR assays targeting SIV Gag. Neuroinflammation was assessed by flow cytometry and multiplex ELISA assays.ResultsRNA sequencing and flow cytometry data demonstrated immune surveillance of the rhesus CNS by innate and adaptive immune cells during homeostasis. Following SHIV infection, viral entry and integration within multiple brain regions demonstrated vulnerabilities of key cognitive and motor function brain regions to HIV-1 during the acute phase of infection. SHIV-induced transcriptional alterations were concentrated to the PFCw and STS with upregulation of gene expression pathways controlling innate and T-cell inflammatory responses. Within the PFCw, gene modules regulating microglial activation and T cell differentiation were induced at 28 days post-SHIV infection, with evidence for stimulation of immune effector programs characteristic of neuroinflammation. Furthermore, enrichment of pathways regulating mitochondrial respiratory capacity, synapse assembly, and oxidative and endoplasmic reticulum stress were observed. These acute neuroinflammatory features were substantiated by increased influx of activated T cells into the CNS.ConclusionsOur data show pervasive immune surveillance of the rhesus CNS at homeostasis and reveal perturbations of important immune, neuronal, and synaptic pathways within key anatomic regions controlling cognition and motor function during acute HIV infection. These findings provide a valuable framework to understand early molecular features of HIV associated neurodegeneration.

Project description:We modified a Sabin Oral Poliovirus Vaccine (OPV) vector to permit secretion of the antigens of interest with the goal of improving anti-HIV Env humoral responses in a SHIV mucosal immunization composed of DNA and recombinant OPVs. We evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in Rhesus macaques by two regimens, both involving a prime with a SHIVBG505 DNA construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral cavity, and two different viral vector boostings, administered in the oral cavity and intestinally. Group 1 was boosted with rMVA-SHIVBG505, expressing SIV Gag/Pol and HIVBG505 Env. Group 2 was boosted with a SHIVBG505-OPV vaccine including a non-secreting SIVmac239CA-p6-OPV, expressing Gag CA, NC and p6 proteins, and a HIVBG505C1-V2-OPV, secreting the C1-V2 fragment of HIV EnvBG505, recognized by the broadly neutralizing antibody PG16. A time course analysis of anti-SHIV Gag and Env CD4+ and CD8+ T-cell responses in PBMC and in lymph node, rectal, and vaginal MNC was carried out. Both regimens stimulated significant cell-mediated responses in all compartments, with SHIVBG505-OPV immunization stimulating more significant levels of responses than rMVA- SHIVBG505. Boolean analysis of these responses revealed predominantly monofunctional responses with multifunctional responses also present in all tissues. Stimulation of antibody responses was disappointing in both groups with negative anti-SHIV IgG in plasma, and IgA in salivary, rectal and vaginal secretions being restricted to a few animals. After repeated rectal challenge with SHIVBG505, two Group 1 animals remained uninfected at challenge termination. No significant differences were observed in post-infection viral loads between groups. After the acute phase decline, CD4+ T cell percentages returned to normal levels in vaccinated as well as control animals. However, when compared to controls, vaccinate groups had more significant preservation of PBMC and rectal MNC Th17/Treg ratios, considered the strongest surrogate marker of progression to AIDS. We conclude that the vaccine platforms used in this study are insufficient to stimulate significant humoral immunity at the tested doses and schedule but sufficient to stimulate significant mucosal and systemic cell-mediated immunity, impacting the preservation of key Th17 CD4+ T cells in blood and rectal mucosa.

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Vaccination-induced noncytolytic effects in the acute phase of SHIV infection.

Publications

Vaccination-induced noncytolytic effects in the acute phase of SHIV infection.

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