Immunity to retroviral infection: The Friend virus model

140

The biologically active form of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein is oligomeric. We previously described a soluble HIV-1 IIIB Env protein, gp140, with a stable oligomeric structure composed of uncleaved gp120 linked to the ectodomain of gp41 (P. L. Earl, C. C. Broder, D. Long, S. A. Lee, J. Peterson, S. Chakrabarti, R. W. Doms, and B. Moss, J. Virol. 68:3015-3026, 1994). Here we compared the antibody responses of rabbits to gp120 and gp140 that had been produced and purified in an identical manner. The gp140 antisera exhibited enhanced cross-reactivity with heterologous Env proteins as well as greater neutralization of HIV-1 compared to the gp120 antisera. To examine both immunogenicity and protective efficacy, we immunized rhesus macaques with oligomeric gp140. Strong neutralizing antibodies against a homologous virus and modest neutralization of heterologous laboratory-adapted isolates were elicited. No neutralization of primary isolates was observed. However, a substantial fraction of the neutralizing activity could not be blocked by a V3 loop peptide. After intravenous challenge with simian-HIV virus SHIV-HXB2, three of the four vaccinated macaques exhibited no evidence of virus replication.

mentioning

confidence: 98%

Immunogenicity and Protective Efficacy of Oligomeric Human Immunodeficiency Virus Type 1 gp140

Earl

Sugiura

Montefiori

et al. 2001

140

“…ϩ CTL, and CD4 ϩ T-cell responses that are generated during acute infection (7,30). Evidence indicates that this escape occurs very early in infection and is probably related to the infection of a small population of B cells (15,16,28).…”

Section: Cd4mentioning

confidence: 99%

CD4⁺T Cells and Gamma Interferon in the Long-Term Control of Persistent Friend Retrovirus Infection

Iwashiro

Peterson

Messer

et al. 2001

Self Cite

We have used the Friend virus model to determine the basic mechanisms by which the immune system can control persistent retroviral infections. Previously we showed that CD4 ؉ T cells play an essential role in keeping persistent retrovirus in check. The present in vitro experiments with a Friend virus-specific CD4 ؉ T-cell clone revealed that these cells produce gamma interferon (IFN-␥), which acts with two distinct mechanisms of antiviral activity. First, IFN-␥ had a direct inhibitory effect on virus production. This inhibitory effect was noncytolytic and, interestingly, was not associated with decreased cell surface expression of viral antigens. The second mechanism of IFN-␥-mediated antiviral activity was an enhancement of CD4 ؉ T-cell-mediated cytolytic activity. We also found an in vivo role for IFN-␥ in the control of persistent Friend virus infections. Neutralization of IFN-␥ in persistently infected mice resulted in significantly increased levels of virus in the spleen, and a significant percentage of IFN-␥-deficient mice were unable to maintain long-term control over Friend virus infections.The most serious problems caused by many retroviruses often result from the effects of persistent infection rather than the initial acute phases of infection. For example, the acute phase of infection with human immunodeficiency virus (HIV) is generally resolved relatively quickly, but the virus persists and after several years results in diminished CD4ϩ T-cell levels, loss of immune functions, and the onset of AIDS. As a model for studying persistent retrovirus infections, we have used Friend virus complex (FV) in strains of mice which generally recover from acute disease but develop lifelong, lowlevel persistent infections (6, 28). Many types of cells including erythroid precursors, monocytes, and lymphocytes are initially infected with FV during the acute phase of disease (28). Recovery from the acute phase is dependent on genes of the major histocompatibility complex (MHC) and complex immune responses including cytotoxic T-lymphocyte (CTL), CD4 ϩ T-helper, and antibody responses (reviewed in references 30 and 31). Following recovery from FV-induced splenomegaly and viremia, the infection in the spleen is reduced by over 1,000-fold and appears to be primarily restricted to a very small population of B cells (28).Most persistently infected mice live a normal life span, although for unknown reasons, approximately 5% of the mice eventually relapse with FV-induced erythroleukemia (6). Unlike HIV, FV infection does not deplete CD4 ϩ T-cell levels, but if mice with persistent FV are experimentally depleted of their CD4ϩ T cells, a large percentage of the mice relapse with acute disease and develop erythroleukemia (28). Thus, CD4 ϩ T cells play a critical role in containing persistent FV infections. In contrast, depletion of CD8 ϩ T cells does not induce relapse or increased levels of persistent virus, nor is there an additive effect from dual depletion of both CD4 ϩ and CD8 ϩ T cells (28). Furthermore, CD4 depletions do ...

“…In susceptible strains, disease progresses to lethal erythroleukemia (46,49,70). Both virus-specific cellular and humoral immune responses are essential for recovery from primary FV infection (25,27,60,67). Furthermore, vaccine-induced protection against FV-induced erythroleukemia also requires complex immune responses including CD4 ϩ T cells (Th cells); CD8 ϩ T cells (cytolytic T lymphocytes [CTL]), and B cells (17).…”

mentioning

confidence: 99%

Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection

Dittmer

Peterson

Messer

et al. 2001

Self Cite

The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-␥), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4-and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-␥-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-␥-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-␥ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.