HCV & HIV Specific CD4 Response

Two Articles:


2. Recurrence of Hepatitis C Virus After Loss of Virus-Specific CD4(+) T-Cell Response in Acute Hepatitis C

Gastroenterology 1999 Oct;117(4):933-941

Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, Hoffmann R, Schirren CA, Santantonio T, Pape GR Institute for Immunology, Klinikum Groshadern, University of Munich, Germany.
[Record supplied by publisher]

Background & Aims: The prospective comparison of patients with acute hepatitis C virus (HCV) who spontaneously clear the virus with those who cannot achieve viral elimination and progress to chronic hepatitis offers the unique opportunity to analyze natural mechanisms of viral elimination. Methods: We studied the HCV-specific CD4(+) T-cell response in 38 patients with acute HCV and correlated the clinical course with the antiviral immune response. The individual HCV-specific T-cell response was assessed in a proliferation assay ((3)H-thymidine uptake) and an enzyme-linked immunospot assay. Results: Patients were classified according to their clinical course and pattern of CD4(+) T-cell responses in 3 categories: first, patients mounting a strong and sustained antiviral CD4(+)/Th1(+) T-cell response who cleared the virus (HCV RNA-negative; n = 20); second, patients who were unable to mount an HCV-specific CD4(+) T-cell response and developed chronic disease (n = 12); and third, patients who initially displayed a strong CD4(+) T-cell response and eliminated the virus (HCV PCR-negative) but subsequently lost this specific T-cell response (n = 6). The loss of the HCV-specific CD4(+) T-cell response was promptly followed by HCV recurrence. Conclusions: The results indicate that a virus-specific CD4(+)/Th1(+) T-cell response that eliminates the virus during the acute phase of disease has to be maintained permanently to achieve long-term control of the virus. The induction and/or maintenance of virus-specific CD4(+) T cells could represent a promising therapeutic approach in HCV infection.


SAN DIEGO, CA, October 26, 1998 -- Epimmune Inc., a majority-owned subsidiary of Cytel Corporation (NASDAQ: CYTL), today announced that it has received two Phase II Small Business Innovation Research (SBIR) grants totaling $1.5 million from the National Institutes of Health (NIH) to investigate a new approach for treating and preventing viral infections. The two studies are aimed at extending into non-human primate models the preclinical evidence that Epimmune’s technology enables the induction of specific immune responses critical to controlling hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections.

In spite of recent breakthroughs in anti-viral therapy, developing cures for HCV, HIV and other viral infections remain unrealized goals. “Viruses are extremely resilient. They use a variety of strategies to divert the immune response and to persist through months of direct attack by anti-viral drugs,” said Robert W. Chesnut, Ph.D., Executive Vice President, Research and Development of Epimmune.

“Since the human immune system is capable of preventing these viruses from becoming established, as well as clearing them once established, we have focused on understanding and mimicking these beneficial immune mechanisms,” added Dr. Chesnut. “In particular, CD8+ killer T-cells (CTL) and CD4+ helper T-cells (HTL) have been shown to be the critical components of the body’s natural defense against infectious diseases including HCV and HIV. Based on extensive studies of the key receptors that control these immune responses, we think we have figured out how to design ‘smart vaccines’ that will redirect the immune response in such a way that it will effectively attack the virus and eliminate the infection.”

To this end, Epimmune scientists have identified specific viral fragments, known as epitopes, from the hepatitis C and AIDS viruses, capable of stimulating CTL and HTL. Epimmune’s candidate vaccines are comprised of multiple epitopes from the targeted virus, selected to focus the immune system on killing the virus while avoiding non-productive or even counter-productive immune responses.

The NIH grant directed toward HCV vaccine research is a two-year program entitled “Vaccine Approaches to Treatment of Hepatitis C Infection (HCV).” Under the grant, Epimmune will evaluate the feasibility of using chimpanzees to test its epitope-based vaccine candidates. After validating the chimp as an appropriate model, Epimmune plans to test the ability of its HCV genetic vaccines to elicit a cellular immune response targeted to multiple HCV epitopes and determine whether this response can protect against, or alter the course of, an HCV infection in primates.

The NIH grant directed toward AIDS vaccine research is a two-year program entitled “Peptide-Based Vaccine for Primate Model of AIDS,” to be conducted in collaboration with David I. Watkins, Ph.D., Associate Professor of the Wisconsin Regional Primate Research Center. Under the grant, the investigators will evaluate the ability of epitope-based genetic vaccines to elicit a cellular immune response in macaques monkeys targeted to multiple epitopes from simian immunodeficiency virus (SIV), an AIDS-like virus, and determine whether this response can protect against, or alter the course of, the viral infection. Epimmune Inc., established in October 1997, is a majority-owned subsidiary of Cytel Corporation (NASDAQ: CYTL), operating under separate management and financing. Applying its substantial immunology expertise and scientific leadership in the field of T-cell recognition and activation, Epimmune is developing novel vaccines which stimulate the body’s immune system to treat and prevent infectious diseases and cancer. Epimmune is collaborating with G.D. Searle & Co., a wholly-owned subsidiary of Monsanto Co., to develop immune stimulating products for the treatment of cancer. Additional product targets include prophylactic vaccines for hepatitis C, HIV and malaria and therapeutic vaccines for hepatitis B, hepatitis C and HIV.