DNA vaccine encoding human immunodeficiency virus-1 Gag, targeted to the major histocompatibility complex II compartment by lysosomal-associated membrane protein, elicits enhanced long-term memory response

ABSTRACT We investigated long-term memory and recall cellular immune responses to human immunodeficiency virus type 1 (HIV-1) Env and Gag proteins elicited by recombinant vesicular stomatitis viruses (VSVs) expressing Env and Gag. More than 7 months after a single vaccination with VSV-Env, ∼6% of CD8+ splenocytes stained with major histocompatibility complex class I tetramers containing the Env p18-I10 immunodominant peptide and showed a memory phenotype (CD44Hi). The level of tetramer-positive cells in memory was about 14% of the peak primary response. Recall responses elicited in these mice 5 days after boosting with a heterologous recombinant vaccinia virus expressing HIV-1 Env showed that 40 to 45% of CD8+ splenocytes were tetramer positive and activated (CD62LLo), and these cells produced gamma interferon after stimulation with Env peptide, indicating that they were functional. Five months after the boost, the long-term memory cell population (tetramer positive, CD44Hi) constituted 30% of the CD8+ splenocytes. Recall responses to HIV-1 Gag were examined in mice primed with VSV recombinants expressing HIV-1 Gag protein and boosted with a vaccinia virus recombinant expressing Gag. Using this protocol, we found that ∼40% of CD8+ splenocytes were activated (CD62LLo) and specific for a Gag immunodominant peptide (tetramer positive). The high-level Gag recall response elicited by the vaccinia virus-Gag was greater than that obtained by boosting with a VSV-Gag vector with a different VSV glycoprotein. The corresponding levels of CD44Hi memory cells were also higher long after boosting with vaccinia virus-Gag than after boosting with a glycoprotein exchange VSV-Gag. Our results show that VSV vectors elicit high-level memory CTL responses and that these can be amplified as much as six- to sevenfold using a heterologous boosting vector.

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Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules.

Journal of Experimental Medicine ◽

10.1084/jem.175.6.1417 ◽

1992 ◽

Vol 175 (6) ◽

pp. 1417-1422 ◽

Cited By ~ 73

Author(s):

S Kozlowski ◽

M Corr ◽

T Takeshita ◽

L F Boyd ◽

C D Pendleton ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Major Histocompatibility Complex ◽

T Cell ◽

Class I ◽

Converting Enzyme ◽

Major Histocompatibility ◽

Free System ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

Human Immunodeficiency Virus 1

T cell stimulation by the human immunodeficiency virus 1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules in a cell-free system was found to require proteolytic cleavage. This extracellular processing was mediated by peptidases present in fetal calf serum. In vitro processing of p18 resulted in a distinct reverse phase high performance liquid chromatography profile, from which a biologically active product was isolated and sequenced. This peptide processing can be specifically blocked by the angiotensin-1 converting enzyme (ACE) inhibitor captopril, and can occur by exposing p18 to purified ACE. The ability of naturally occurring extracellular proteases to convert inactive peptides to T cell antigens has important implications for understanding cytotoxic T lymphocyte responses in vivo, and for rational peptide vaccine design.

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Faculty Opinions recommendation of Serum angiotensin-1 converting enzyme activity processes a human immunodeficiency virus 1 gp160 peptide for presentation by major histocompatibility complex class I molecules.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.723625726.793515674 ◽

2016 ◽

Author(s):

Kenneth Bernstein

Keyword(s):

Human Immunodeficiency Virus ◽

Enzyme Activity ◽

Major Histocompatibility Complex ◽

Major Histocompatibility Complex Class ◽

Class I ◽

Complex Class ◽

Converting Enzyme ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

Human Immunodeficiency Virus 1

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Group-specific, major histocompatibility complex class I-restricted cytotoxic responses to human immunodeficiency virus 1 (HIV-1) envelope proteins by cloned peripheral blood T cells from an HIV-1-infected individual.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.85.22.8638 ◽

1988 ◽

Vol 85 (22) ◽

pp. 8638-8642 ◽

Cited By ~ 67

Author(s):

S. Koenig ◽

P. Earl ◽

D. Powell ◽

G. Pantaleo ◽

S. Merli ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Major Histocompatibility Complex ◽

Infected Individual ◽

Complex Class ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

Cytotoxic Responses ◽

Hiv 1 ◽

Human Immunodeficiency Virus 1

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Infection of CD127+ (Interleukin-7 Receptor+) CD4+ Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.00249-06 ◽

2006 ◽

Vol 80 (20) ◽

pp. 10162-10172 ◽

Cited By ~ 62

Author(s):

John J. Zaunders ◽

Susanna Ip ◽

Mee Ling Munier ◽

Daniel E. Kaufmann ◽

Kazuo Suzuki ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Regulatory Cells ◽

Long Term Memory ◽

Regulatory Cells ◽

Term Memory ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT We recently found that human immunodeficiency virus (HIV)-specific CD4+ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38+++CD4+ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4+ T cells also expressed CD127, a marker of long-term memory cells. Purified CD127+CD4+ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4+ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4+ T cells in vitro and only a small increase in CD45RO+CD25+CD127dimCD4+ T regulatory cells during PHI. However, 40% of CCR5+CD38+++ CD4+ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4+ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4+ T cells is associated with a combination of an infection of CCR5+ CD127+ memory CD4+ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.

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