Multigene DNA Priming-Boosting Vaccines Protect Macaques from Acute CD4
            <sup>+</sup>
            -T-Cell Depletion after Simian-Human Immunodeficiency Virus SHIV89.6P Mucosal Challenge

et al. 2008

J Virol

Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzymelinked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4 ؉ and CD8 ؉ T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4 ؉ T-cell response (NYVAC). Remarkably, vector-induced differences in CD4 ؉ /CD8 ؉ T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4 ؉ T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4 ؉ T-cell responses showed efficacies similar to those with stronger CD8 ؉ T-cell responses.

Section: Discussionmentioning

confidence: 99%

Differential CD4⁺versus CD8⁺T-Cell Responses Elicited by Different Poxvirus-Based Human Immunodeficiency Virus Type 1 Vaccine Candidates Provide Comparable Efficacies in Primates

Mooij

Balla-Jhagjhoorsingh

et al. 2008

J Virol

“…However, several vaccination protocols have achieved preservation of CD4 + T cells (Amara et al, 2001;Barouch et al, 2000;Doria-Rose et al, 2003;Mooij et al, 2004;Shiver et al, 2002;Takeda et al, 2003;Voss et al, 2003), including the CD4 + memory subsets (Nishimura et al, 2004). A unique opportunity is thus provided to study immune activation and its relationship to the establishment of a set-point virus load in the absence of memory T-cell loss.…”

Section: Introductionmentioning

confidence: 99%

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

Journal of General Virology

Mortier

Hofman

et al. 2009

Human immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV)infection in macaques are accompanied by a combined early loss of CCR5 (CD195)-expressing CD4 + memory T cells, loss of T-helper function and T-cell hyperactivation, which have all been associated with development of high virus load and disease progression. Here, a cohort of vaccinated simian-human immunodeficiency virus strain 89.6p (SHIV 89.6p )-infected rhesus macaques, where preferential depletion of these memory T-cell subsets does not take place and CD4 + T cells are relatively well maintained, was used to study the role of hyperactivation as an independent factor in the establishment of set-point virus load. In the acute phase of the infection, a transient loss of CD4 + T cells, as well as strong increases in expression of proliferation and activation markers on CD4 + and CD8 + T cells, together with CD152 expression on CD4 + T cells, were observed. Peak expression levels of these markers on CD4 + T cells, but not on CD8 + T cells, were correlated with high virus replication in the chronic phase of the infection. In addition, the peak expression level of these markers was correlated inversely with acute-phase, but not chronic-phase, HIV/SIV-specific gamma interferon responses. These data highlight a central role for an acute but transient CD4 decrease, as well as CD4 + T-cell activation, as independent factors for prediction of set-point levels of virus replication. INTRODUCTIONHuman immunodeficiency virus (HIV) infection in humans and simian immunodeficiency virus (SIV) infection in rhesus macaques are typically characterized by a slow, progressive loss of CD4 + T cells leading to immune incompetence and the onset of opportunistic infections (Fauci, 1988;Lifson et al., 1988). However, already by the early stages of infection, gut-homing CCR5-expressing CD4 memory subsets are being depleted (Brenchley et al., 2004;Li et al., 2005;Mattapallil et al., 2005Mattapallil et al., , 2004Veazey et al., 1998Veazey et al., , 2000 and CD4 + T-helper cell function is impaired (Clerici & Shearer, 1993; Koopman et al., 2001;Lane et al., 1985;McKay et al., 2003;Meyaard et al., 1996;Miedema et al., 1988;Shearer & Clerici, 1991). Recently, both events were found to be associated with the development of high virus load in SIVinfected macaques (Sun et al., 2007). Besides a possible direct immunosuppressive effect exerted by several HIV proteins (Cefai et al., 1992;Schindler et al., 2006;Westendorp et al., 1995), the formation of regulatory T cells, specifically the thymus-derived CD25 hi /FOXP3 + /CD152 + subset (Andersson et al., 2005;Estes et al., 2006;Hryniewicz et al., 2006;Kinter et al., 2004;Leng et al., 2002;Nilsson et al., 2006;Tsunemi et al., 2005), was found to be increased in HIV as well as in SIV infection, and was shown to contribute to suppression of HIV-specific immune responses (Kinter et al., 2004;Nilsson et al., 2006;Tsunemi et al., 2005).On the other hand, HIV infection induces a state of chronic immune activatio...

“…DNA vaccines were shown to induce both humoral and cellular immune responses in rodents, but in non-human primates and in humans, only low-level immunogenicity has been reported (Estcourt et al, 2004;Robinson, 1999). Efforts have been directed at improving these responses by boosting with viral vectors (Amara et al, 2002;Brave et al, 2007;Casimiro et al, 2005;Doria-Rose et al, 2003;Hel et al, 2006;Koopman et al, 2004;Letvin et al, 2004). DNA vaccines are generally effective at stimulating CD8 responses, whilst subunit vaccines are more effective at eliciting antibody responses (Barouch et al, 2000;Earl et al, 2001Earl et al, , 2002Patterson et al, 2004;Robinson, 1999).…”

Section: Introductionmentioning

confidence: 99%

Immune-response profiles induced by human immunodeficiency virus type 1 vaccine DNA, protein or mixed-modality immunization: increased protection from pathogenic simian–human immunodeficiency virus viraemia with protein/DNA combination

Journal of General Virology

Mortier

Hofman

et al. 2008

Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be most efficacious if they elicit a combination of adaptive humoral and T-cell responses. Here, we explored the use of different vaccine strategies in heterologous prime–boost regimes and evaluated the breadth and nature of immune responses in rhesus monkeys induced by epidermally delivered plasmid DNA or recombinant HIV proteins formulated in the AS02A adjuvant system. These immunogens were administered alone or as either prime or boost in mixed-modality regimes. DNA immunization alone induced cell-mediated immune (CMI) responses, with a strong bias towards Th1-type cytokines, and no detectable antibodies to the vaccine antigens. Whenever adjuvanted protein was used as a vaccine, either alone or in a regime combined with DNA, high-titre antibody responses to all vaccine antigens were detected in addition to strong Th1- and Th2-type CMI responses. As the vaccine antigens included HIV-1 Env, Nef and Tat, as well as simian immunodeficiency virus (SIV)mac239 Nef, the animals were subsequently exposed to a heterologous, pathogenic simian–human immunodeficiency virus (SHIV)89.6p challenge. Protection against sustained high virus load was observed to some degree in all vaccinated groups. Suppression of virus replication to levels below detection was observed most frequently in the group immunized with protein followed by DNA immunization, and similarly in the group immunized with DNA alone. Interestingly, control of virus replication was associated with increased SIV Nef- and Gag-specific gamma interferon responses observed immediately following challenge.