Expert opinion suggests that an effective preventative vaccine against HIV-1 infection will require both cellular and humoral immunity to achieve protection (Mooij et al., 2001). However, which T-cell responses are critical for protection remain unanswered, furthermore the ability of a vaccine to generate neutralising antibodies remains elusive (MacMichael A, 2006). The added challenge will be to devise a vaccine with sufficient breadth to deal with the different HIV-1 clades encountered around the world. Vaccines can additionally be used therapeutically in those already infected to induce or augment an individual’s response to infection, as first proposed by Salk in 1987 (Salk et al., 1987).
Detailed immunological profiling of LTNP has identified various parameters conducive to delayed progression of HIV-1 infection (Deeks et al., 2007). This provides targets for immune manipulation in an attempt to recreate this milieu in HIV-1 infected individuals. The advent of cART has created an environment more permissive to achieving these aims. Prior to the introduction of cART and effective plasma viral suppression, vaccination- induced activation of T-cells provided targets for the virus present in the
plasma. Effective cART has, by viral suppression, minimised this threat, and enhanced its potential as a therapeutic agent.
Initial therapeutic vaccine studies focused on attempts to induce blocking antibodies. Although successful in animal models, trials of agents such as recombinant gp 120 immunogen have proved less successful in humans infected with HIV-1, with no demonstrable clinical benefit (Salk et al., 1987, Ross et al., 2010).
1.4.2 Remune: HIV-1 Immunogen
Remune is one therapeutic vaccine candidate which initially appeared promising, although subsequent clinical data has somewhat dampened the early enthusiasm. As is often the case, favourable immune profiles induced by the immunogen have so far failed to translate into appreciable clinical benefit. Remune (Immune Response Corp. (IRC), San Diego CA) is a whole, inactivated, gp120 depleted immunogen suspended in incomplete Freund’s adjuvant (IFA) (Moss et al. 1994, Trauger et al., 1994). It is based on clade A env and clade G gag from the recombined Zairian primary isolate HZ-321 and grown in the HuT-78 cell line (Moss et al., 1998). It has been administered to more than 3000 trial patients, and appears to be safe and well tolerated (Levine et al., 1996, Churdboonchart et al., 2000, Chantratita et al., 2004). It is administered at doses of 50-400µg total protein, by intramuscular injection at twelve week intervals. Typical reported side effects include flu-like symptoms and local injection site reactions. Several studies have demonstrated improvement in various immunological parameters, including a beneficial effect on CD4 T-cell count and viral load (Turner et al., 2001, Sukeepaisarncharoen et al., 2001, Chantratita et al., 2004). Its use is associated with enhancement of HIV-1 specific delayed type hypersensitivity
(DTH) responses and lymphocyte proliferative responses (LPR) (Valentine et al., 1996, Churdboonchart et al., 2000, Turner et al., 2001, Robbins et al., 2003). It increases levels of IFN (TH1 cytokine) and chemokines (Moss et al., 1997, Valentine et al., 1998). It has been shown to augment cell mediated immune (CMI) responses to autologous virus and increased antibody reactivity has been described; both strength and breadth of Western Blot (WB) reactivity (Churdboonchart et al., 2000).
The first clinical study of Remune in 1994 was a phase one, dose ranging study in ARV naïve HIV-1 infected individuals which showed improved HIV-1 specific DTH and antibody response (Turner et al., 1994). A subsequent study (Levine et a., 1996) demonstrated improved DTH in approximately 50% of the 25 patients, who then went on to have a decreased rate of clinical events and death. This association was potentially biased by the possibly more conserved immune function of those individuals in the more reactive group. An IRC study in 15 patients, demonstrated increases in IFN , chemokines and LPR to HIV-1 specific antigens (Moss et al., 1997). A Thai study of 29 ARV naive individuals, 28 infected with clade E, also showed improvement in WB reactivity in those receiving Remune. A subsequent larger, double-blinded, adjuvant-controlled trial demonstrated increases in CD4 T-cell counts and HIV-1-specific immunogenicity (DTH and WB) (Churdboonchart et al., 2000). Other Thai studies have shown stabilisation of body weight, viral load and CD4 T-cell percentage (Sukeepaisarncharoen et al., 2001, Chantratita et al., 2004). Valentine and colleagues reported increased levels of gag-specific T- helper-cell responses (Valentine et al., 1996) and β chemokines (Valentine et al., 1998)) comparable to that seen in LTNP, along with a greater proportion of individuals achieving viral loads BLD in those receiving Remune. Others
have also observed increases in HIV-1 specific CD4 T-cell proliferative responses (Moss et al., 2000, Robbins et al., 2003).
The largest study to date is a phase three, multicentre, double-blind, placebo controlled, randomised, clinical endpoint trial in 2527 ARVT naïve HIV-1 infected individuals (Kahn et al., 2000). HIV-1 progression-free survival was the primary endpoint with secondary endpoints being overall survival, HIV RNA, CD4 T-cell count and percentage, body weight and immunogenicity. The only difference observed was an increase in the mean CD4 T-cell count, and no difference in clinical outcomes was observed. The publication of these results was controversial due to author disagreement with the sponsoring company regarding analysis and interpretation of the results. Results from a prospectively identified sub-group (n=252) by Moss and colleagues (IRC) revealed the vaccinated group had a significantly greater decline in plasma viral RNA, both in the speed of decline and the percentage of individuals becoming undetectable, and enhanced lymphoproliferative response (LPR) to HIV-1 specific antigens (Moss et al., 2000).
Remune does appear to have potentially beneficial effects. Whether this translates to clinical advantage remains to be seen. Enhancement of the effects observed to date may also be of benefit. We therefore included Remune in the study described in Chapter Four of this thesis to observe its effect on T-cell phenotype and whether these were further influenced by IL-2 immunotherapy.
CHAPTER TWO: MATERIALS AND METHODS