Family Practice Vol. 18, No. 2, 230-235
© Oxford University Press 2001
Selections from Current Literature |
Recent developments in human HIV-1 vaccine
Department of Family Medicine, Health Science Center L-4, State University of New York at Stony Brook, Stony Brook, NY 11794, and
a Columbia University School of Nursing, USA.
D Dabelstein, MD
Dabelstein D and Cromer B. Recent developments in human HIV-1 vaccine. Family Practice 2001; 18: 230–235.
This article reviews recent changes in the design of HIV-1 vaccine. The safety information for current vaccines has been established, and future ethical considerations are reviewed. Of recent significance, gp120 envelope vaccines are being combined with canarypox vectors in an attempt to elicit a broad immune response. This will probably be the aim of future research for an ever-growing problem. A total of 10 143 AIDS cases have occurred in the USA in the year 2000.1 The international burden is grimmer. For example, approximately 13% of South Africans between 20 and 64 years old are HIV positive. Predictions estimate this number to rise to almost 30% by 2010.2 With many different HIV serotypes, a worldwide effective HIV vaccine is not in the near future.3 However, the scientific community has bolstered its effort by strengthening resources and developing national and international collaboration groups focused on developing a safe and effective HIV vaccine.
Ethics
Bayer R. Ethical challenges of HIV vaccine trials in less developed nations: conflict and consensus in the international arena. AIDS 2000; 14: 1051–1057.
This article reviews important ethical issues of HIV vaccine research identified by the Joint United Nations Program on AIDS (UNAIDS). Essentially, the issues revolve around the fact that poor nations, which are the most vulnerable to HIV, are in jeopardy of being exploited by research due to their inability to set standards to protect research participants. The author identifies informed consent, access to treatment, and ethical review by the host nation as three major topics of debate which the UNAIDS programme deemed important when considering HIV vaccine research.
The challenges of informed consent are related to cultural, educational and language differences that exist between researchers and volunteers. Explaining various informed consent issues such as the purpose of a placebo, the meaning of randomization, and a volunteer's right not to participate or to withdraw from a trial at any time is difficult, and without a thorough understanding is unethical. Other conflicts identified involved the possibility of community leaders agreeing to allow for the participation of the entire community without the informed consent of each individual within that community, or the inability of community members to participate because participation was forbidden by community leaders. The author points out that some cultures forbid women from participating in research without the approval of their husbands or families. Another issue involves whether pregnant women should be allowed to con-sent or be a basis for exclusion from HIV vaccine research due to the possible damaging effects of HIV vaccines.
An area of intense debate is related to the level of care research participants should have access to in the event they develop HIV infection during a vaccine trial. Essentially the question is whether volunteers' treatment is based on the clinical standards of a third world country or based on the standard of care of industrialized countries. Those who favour the best possible treatment cite the Declaration of Helsinki, which states that control groups must be provided with the best current treatment. Supporters of the best possible treatment also point out the potential for exploitation of third world countries for research purposes, because the research could not be carried out in industrialized countries due to financial constraints. Those who favour treatment at the level of the host country argue that there is no ‘imperative’ to treat participants with the treatment available in the sponsoring nation, and these treatment regimes were non-sustainable in poor nations.
Finally, the author reviews the standards set forth by the Council for International Organizations of Medical Sciences which supports an effective ethical review mechanism that ensures the ethical standards of the host and sponsoring nation. The author also raises the question of whether a host country is permitted to conduct research, which they take to be ethically acceptable, but which has failed ethical review in the sponsoring nation.
Comments
Even though the literature is inundated with HIV vaccine studies, there is little emphasis on ethical considerations involved in international HIV vaccine research. With so much at stake, national and international authorities are bolstering research support in an effort to prevent the astonishing spread of this elusive virus. One particular driving force that may cloud the ethics of clinical research is the potential monetary gain by the institution or body which develops an effective vaccine. It is predominantly pharmaceutical companies driving vaccine research. This may create conflicts of interest in investigators who receive industry support. A basic premise of informed consent is that volunteers must understand the difference between clinical research and treatment—indeed, a complex task when languages and cultures are the same, and even more difficult when they differ. Complicating matters further is the false sense of hope volunteers may develop when participating in trials. Volunteers from poor countries may have inaccurate perceptions of the purpose of studies; they may think that they are being protected from disease, and therefore participate in risky behaviour more frequently. It is unethical to place volunteers at unknown risk without them fully understanding the possibilities of harm. Although HIV vaccine research is imperative, as clinicians, it is our moral and professional responsibility to ensure adherence to the highest ethical standards of clinical research no matter when, where or how research is being conducted. As the Tuskegee Syphilis Study and others have illustrated, ethical considerations can be easily clouded by the goal of obtaining clinical data.4
Safety
Keefer MC, Wolff M, Gorse GJ et al. Safety profile of Phase I and II preventive HIV Type 1 envelope vaccination: experience of the NIAID AIDS Vaccine Evaluation Group. AIDS Research and Human Retroviruses 1997; 13(14): 1163–1177.
The authors review data on adverse reactions associated with envelope-based preventative HIV vaccines tested by the AIDS Vaccine Evaluation Group (AVEG) in the USA. Data was collected in an unblinded fashion during 25 phase I (n = 1102) and one phase II (n = 296) multicentred, randomized, double-blind studies. All but three studies were placebo controlled. Participants were 1398 HIV-negative, healthy adult volunteers with no underlying co-morbidities. Vaccine preparations evaluated include envelope proteins rgp160, Env 2–3 and rgp120; peptides V3 loop of gp120 (15 strains); and Pox-vectored recombinants vaccinia gp160, canarypox gp160. Altogether, 17 different preparations with varying adjuvants, dosages, routes and schedules were evaluated. Haematological, hepatic and renal function indices were collected at baseline and throughout the study duration. Data on acute, local and systemic reactions were collected during varying 18–36 month vaccination protocols and during a minimum of 6 months after the final immunization.
Sixty-seven subjects were withdrawn from the studies due to significant reactions or intercurrent events. The authors report that there were no life-threatening immediate anaphylactic type reactions 1 hour after vaccination. One volunteer experienced urticarial rash after the fourth dose of 1200 µg of the V3 peptide preparation, which resolved with antihistamines.
Significant local and systemic reactions did not differ between recipients of envelope protein/peptide vaccines versus those of the control groups. The authors report that "most, if not all, of the reactogenicity observed to date has been associated with the adjuvant component of the vaccine preparations rather than the HIV-1 antigens". Three adjuvants, aluminium hydroxide, MTP-PE and QS21, were associated with moderate or severe acute local injection site reactions. Aluminium hydroxide was associated with moderate to severe pain and tenderness which was self-limiting, as well as vasovagal reactions in four subjects. Two subjects withdrew due to the discomfort associated with the aluminium hydroxide vaccine. MTP-PE, according to the authors, is a synthetic lipophilic derivative of a naturally occurring compound muramyl dipeptide, administered in an oil and water emulsion. MTP-PE was associated with severe local and systemic reactions in over 80% of subjects. Systemic reactions included febrile, flu-like syndrome. The authors report that all reactions were self-limited, requiring symptomatic treatment, and resolved within 24 –72 hours. Four subjects dropped out due to reactions related to MTP-PE. QS21 is a compound derived from the soapbark tree, Quillaja saponaria, and was associated with moderate to severe local pain/tenderness, which resolved within minutes to a few hours after injection. QS21 was also associated with moderate to severe erythema and induration. No volunteers withdrew from the QS21 studies. Intramuscular administration of canarypox gp160 was associated with low level acute reactogenicity. No acute complications related to scarification of vaccinia gp160 were observed.
No significant changes in haematological, hepatic or renal function were observed when compared with controls. Two subjects experienced self-limited haemolytic anaemia. One after receiving 100 µg of V3 peptide vaccine, and the other after the fourth injection of a control preparation containing aluminium. Association with vaccination could not be absolutely excluded. Five volunteers experienced asymptomatic, transient thrombocytopenia and a relationship to vaccination was unclear. Transient elevations of creatine kinase were observed in some groups receiving several different adjuvants; however, any association with vaccination was unclear and the authors report that it was most likely to be due to strenuous physical activity. Eleven subjects receiving experimental HIV vaccine and two subjects receiving control preparations had an unexplained decline in CD4 lymphocyte number (<300 cells/µl). One subject developed absolute lymphopenia within 1 year of receiving her fourth dose of 600 µg of rgp120 in aluminium. Intercurrent HIV infection was ruled out and a relationship to the vaccine was unclear.
The authors observed no unusual difference in the incidence of serious infection between experimental and control subjects. Six volunteers experienced new dermatological manifestations, including localized herpes zoster, pruritic maculopapular rashes (placebo with aluminium adjuvant) and non-pruritic papular rash with arthralgias, malaise and fatigue (rgp160 in aluminium plus Immuno-AG). Two subjects experienced rheumatological manifestations including progressive stiffening of the joints (rgp120). Ten subjects receiving experimental vaccines and one receiving a control developed malignant or pre-malignant tumors. One subject developed synovial cell sarcoma (vaccinia gp160 and boosted with gp160 in alum) and another developed desmoplastic small round cell tumour (rgp120 in MF59).
The authors collected data on 16 pregnancies in women who received one to six injections before becoming pregnant. Six pregnancies resulted in normal spontaneous deliveries of healthy infants, four pregnancies resulted in early trimester spontaneous abortions, and five pregnancies resulted in elective abortions. No congenital malformations were reported.
Intercurrent HIV-1 infections were identified in 16 subjects receiving experimental vaccines and four who were receiving the placebo. The authors report, "at this time there are no apparent differences in the development of immune deficiency and disease in the experimental subjects who became infected after vaccination and other cohorts of infected individuals".
Nine subjects have died since the beginning of the studies. Two expired as a result of malignancies, two by suicide, two due to homicide, one due to an accident, one due to opiate overdose and one due to sudden cardiac death.
Comments
Because of the global cost of HIV, there is intense pressure to develop a vaccine. As a result, safety and efficacy data are being collected together instead of independently. Because of the many different vaccination protocols, including different dosages, adjuvants, routes, timing and boosters, it is difficult to draw any conclusions from safety data without well-designed, double- blind, placebo-controlled studies targeted at collecting data specifically on safety.
Even though human HIV vaccines have been in development for more than a decade, little is known about the safety, tolerability and effectiveness of current candidate human HIV vaccines. Most vaccines used today are whole killed or live attenuated. However, recent evidence shows that live attenuated AIDS vaccines have produced an AIDS-like disease in the rhesus macaque animal model.5 Therefore, attenuated vaccines may not be safe in humans. Furthermore, preliminary evidence suggests that recombinant vaccines that have been tested in humans do not cause HIV-1 infection or AIDS-like disease.6 Long-term follow-up data on malignancy, infection, neurological and immunological involvement, as well as hepatic, renal and gastrointestinal involvement are needed. Safety should be of primary concern when conducting HIV vaccine trials, after all who knew that the rotavirus vaccine would cause intusucception?
Antibody response of gp120 envelope protein
McElrath J, Corey L, Montefiori D et al. A Phase II study of two HIV Type 1 envelope vaccines, comparing their immunogenicity in populations at risk for acquiring HIV Type 1 infection. AIDS Res Hum Retroviruses 2000; 16: 907–919.
This study evaluates the antibody response to two different envelope vaccines incorporating the gp120 HIV protein. The study was performed in a multicentre, double-blind, adjuvant-controlled trial. Two hundred and ninety-six HIV-negative subjects were recruited from numerous HIV risk categories. Eighty-seven percent were assigned to receive either 50 µg of HIV-1 SF-2/gp120 or 600 µg of HIV-1 MN/gp120 at 0, 1 and 6 months. The remaining 13% received the control. To determine antibody decay, a booster dose was given at either 12 or 18 months. The follow-up time was 4 years, with subjects at that time receiving skin tests to determine T cell-mediated response.
Given that this was a phase II study, the primary purpose was to evaluate safety and tolerability. Reactions to the vaccine were determined at the time of injection, as well as 24 and 48 hours later by phone. Clinical evaluations were done to determine antibody response, neutralizing titres to HIV and lymphoproliferative responses. Individuals who contracted HIV during the trial were excluded from further evaluation. The percentage of individuals who became HIV positive was similar between vaccine and control recipients (5%).
Adverse events were limited to malaise, myalgia, headache, fever and nausea in 9% of vaccine recipients. Raised temperature occurred in <2%, with pain at the injection site in 19%. The MN/gp120 had significantly higher rates of erythema then the SF-2/gp120, perhaps secondary to the larger quantity of immunogen (600 µg).
The vaccines were able to induce anti-gp120 antibodies after the second immunization, with titres reaching 95% response after the third vaccine. The vaccines also elicited anti-V3 antibodies, 87% in SF-2/gp120, and 81% in MN/gp120. When analysed by risk stratification categories, the group admitting to i.v. drug use had significantly lower titres to the anti-gp120 of either vaccine. The researchers then evaluated neutralizing ability to HIV-1. The control group had no ability to neutralize HIV in vitro. After 3–4 immunizations, 99–100% of MN/gp120 and 90–94% of SF-2/gp120 had neutralizing antibodies to HIV. Overall the MN/gp120 had higher neutralizing titres to HIV. As was seen with the antibody response, high-risk groups had lower rates of HIV neutralizing titres.
The investigators then evaluated for decline of titres. The peak titres were irrespective of the dose being given at 12 or 18 months. A total of 140 subjects were retested at 2 years and 53% had persistent titres to homologous virus. Neutralizing ability was low, but greater in the MN/ gp120 arm. Lastly, lymphoproliferative response was analysed at the end of the 4 year follow-up. Both vaccines were able to induce a response, but not in a dose-dependent fashion. Skin testing was done 4 years later in 78 volunteers to evaluate for T cell-mediated delayed type hypersensitivity. Forty-one percent of the SF-2/gp120 and 63% of the MN/gp120 had greater then 10 mm of induration.
Comments
This study does a good job assessing response to HIV-1 immunization, in respect to various higher risk HIV groups. It demonstrated a clear antibody response to envelope antigens with a fair analysis of neutralizing ability and lymphoproliferative response. Four-year follow-up is quite good when compared with other HIV protocols. A smaller number of subjects were followed at that time (78 from 296), which limits the strength of the evidence and applicability to larger populations. The study may also introduce bias based on the fact that it was amended to include the skin testing portion, while no information is given as to how these volunteers were selected. An attempt was made to compare the different envelope vaccines. This is difficult, in that many of the results appeared better for MN/gp120, but the dosage was much higher—600 µg versus 50 µg of SF/gp120. Of significance, higher risk groups had decreased antibody titres, and decreased neutralizing ability. This will need to be qualified further prior to a final vaccine, as higher risk groups have the greatest need for adequate immune response. Finally, neither vaccine had major side effects among the various groups.
Well-designed studies, such as this, will be necessary to establish vaccine components, dosages and immunization schedules. Various vaccines are currently being evaluated to determine the best immunogenic regimens. Indeed, envelope vaccines are currently in phase III clinical trials. These efficacy trials will be critical, as studies such as this one were not designed to evaluate clinical effect.
HIV envelope protein vaccines have come under criticism, as they are not able to induce long-term titres, or neutralize primary isolates of HIV-1. It has been felt that limitations of monomeric gp120 vaccines can be overcome by adding other components. However, there is no basis for choosing which components to include, without evidence that each component or individual serotype is able to induce an adequate immune response.7 In theory, a non-sterilizing antibody response could function as part of an immunization protocol, to allow the immune system adequate time to initiate a cellular immune response.7 Clearly efficacy must be established for envelope vaccines, prior to expectations in a combined modality vaccine. Passive-transfer experiments in animals have shown that immunoglobulin in adequate quantities could protect against SIV in macaques monkeys.8,9
Recent research has elicited possible barriers to HIV envelope antibodies, specifically the structure of the gp120 molecule. The gp120 area on the HIV envelope binds the CD4 cell. Research has focused on pre-attachment antibodies to the gp120 that could prevent initial infection of the CD4 cell. Subsequently it has been realized that the gp120 molecule has structural barriers that prevent antibody binding—hypervariable loops and glycosylation of antigenic surfaces, as well as a maturation of the gp120 binding site, probably once the virion makes contact with the CD4 cell membrane.7 At a molecular level, antibodies would have difficulty preventing transmission at this site. In animal models when the glycosylation sites are altered, there is increased neutralizing antibody response.8,10
It is felt that neutralizing antibodies play a role in preventing immediate infection after HIV exposure. However, the degree of neutralizing antibody in vitro will need to be great to elicit an adequate response in vivo, estimated to be 
99% neutralization.7
Cytotoxic T lymphocyte response to canarypox recombinant vaccine
Evans T, Keefer M, Weinhold K et al. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with Rgp 120 elicits broad and durable CD8 cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis 1999; 180: 290–298.
This study illustrates recent attempts to elicit CD8-mediated immune response. It expands on earlier studies aimed primarily at generating an antibody response to HIV-1. This was a phase I trial of canarypox virus vector that was encoded with vCP 300: MN gp120, IIIB gp41, IIIB gag and protease, LAI pol and LAI nef. The vector was given alone, or with a boost of SF-2 gp120, either simultaneously or after the vector.
This was a randomized, double-blind study involving 140 subjects at low risk for HIV infection. The participants were divided into sevem groups, with three controls per 17 vaccine recipients. Again, volunteers received either the vCP300 alone followed by the SF-2 gp120 or simultaneous injection of both.
CD8 cytotoxic T lymphocyte (CTL) activity was determined by an assay analysing when peripheral blood mononuclear cells (PBMC) were 50% depleted by anti-CD8 monoclonal antibodies. Assays were done 2 weeks after the third and fourth immunizations, as well as 6 months after the last immunization. CTL activity ranged from 40 to 81%, with higher rates of positives at later points in time (12 months). CD8 CTL activity against at least one target was 39% versus 11% in the control group. The controls had no repeatedly positive assays, while 22% of CD8 CTL activity was repeatedly positive. Rates were also higher in the 0, 1, 6, 9 month schedule, than the 0, 1, 3, 6 month schedule.
The authors illustrate a trend that greater CD8 activity was noticed in those receiving vCP 300 with SF-2 gp120, than vCP 300 followed by SF-2 gp120. Simultaneous administration of vCP300 and SF-2 gp120 resulted in greater CD8 CTL response (63%) than all other groups combined. Furthermore, administration of vCP 300 alone for all four immunizations resulted in the lowest activity (18–25%).
Antibody response, as would be expected, was most dependent on the SF-2 gp120 administration. ELISA assessed antibodies to SF-2 gp120, SF-2 gp120 V3 loop, etc. Neutralizing antibody titres were determined as the proportion that was needed to produce 50% protection from in vitro exposure to HIV. Geometric mean titres and neutralizing antibody responses were greatest among those arms receiving SF-2 gp120. Administration of vCP 300 alone resulted in 25–59% neutralizing antibody titres, versus 92–100% for administration with SF-2 gp120. Again, simultaneous administration resulted in a faster antibody response.
Lastly lymphoproliferation of PBMC was evaluated after exposure to HIV envelope antigens. All arms, except controls, resulted in a lymphoproliferative response, without major differences between control arms.
There were no significant differences in the various arms for systemic side effects of pain, induration, erythema and temperature.
Comments
This study had well-designed treatment arms to evaluate a large number of vaccine schedules and timing of vaccine components (canarypox vCP300 and envelope protein SF-2 gp120). A clear response in both antibody titres and CD8 response was illustrated when both components of the vaccine were used. Useful information was gained with regard to simultaneous vaccination efficacy. No down-regulation of response was noted to other vaccine components as included with the SF-2 gp120.
Limiting factors include a smaller number of participants that were recruited (140), with only 17 in each arm of the study. Further, no demographic information is provided. Most importantly, HIV risk is not described, and certainly this may bias results between arms. The length of the study was only 12 months; clearly long-term follow-up would be important to evaluate waning of titres.
Using a canarypox vector is an attempt to induce CD8 cytotoxic T cell lymphocyte activity, while keeping the envelope protein boost to elicit neutralizing antibodies. The canarypox vector enters human cells to express the genes that have been linked to it. Canarypox is nonreplicative in humans and has no risk of infection.11 This is in comparison with vaccinia-based vectors which are able to replicate.
It is felt that long-term non-progressors of HIV mount an extensive T helper cell response.12,13 In a study of prostitutes from Nairobi, 5% are resistant to infection, though there is a high HIV exposure rate. In vitro their cells elicit an HIV-specific immune response in the absence of antibody.14 It is felt that this may be secondary to a strong cytotoxic T cell response.15 It is logical that envelope vaccines would not be strong stimulators of cellular immunity, as CTL activation requires that anti-gen is presented from within a live cell, i.e. canarypox vector.12 Recent research has also demonstrated a direct association between viral load and CTL.12,16 With depletion of CD8 cells in monkeys, there was an increase in plasma viraemia. 8,17
Cytokine profiles after HIV-1 recombinant vaccination
Sabbaj S, Mulligan M, Hsieh R et al. Cytokine profiles in seronegative volunteers immunized with a recombinant canarypox and gp120 prime-boost HIV-1 vaccine. AIDS 2000; 14: 1365–1374.
This study analyses the cytokine and T cell response to HIV-1 immunization. Specifically the authors analysed the subsets of CD4 T cell response—both Th1-mediated, with secretion of IL-2, interferon-
and tumour necrosis factor, and Th2-mediated via IL-4, IL-5, IL-6, IL-10 and IL-13. They accomplished this via PCR of mRNA as well as by stimulating peripheral blood mononuclear cells (PBMC) in vitro with HIV antigens
The investigators recruited volunteers at low risk for HIV infection and immunized seven volunteers with recombinant canarypox vector linked to vCP 205: HIV-1 MN gp120, and then boosted the response with HIV-1 SF-2/gp120. The vaccines were given in an accelerated schedule, at 0, 7, 14 and 21 days with the protein boost days 28 and 84. Two volunteers were given control and then boosted with HIV-1 SF-2/gp120, and three volunteers received control only. To evaluate efficacy, proliferative responses were determined via a saturation index of antigen-stimulated cells. Cytokine levels were determined via ELISA and mRNA was extracted from antigen-stimulated PBMC and amplified via PCR.
The results demonstrated that the lymphoproliferative response peaked 2 weeks after the first HIV-1 SF-2/gp120 boost in those immunized with both the canarypox vaccine and protein boost, as compared with controls. Furthermore, ELISA measured cytokine levels of PBMC. All those that received the prime–boost regimen had detectable interferon- after stimulation of PBMC with HIV envelope proteins. Five had detectable IL-4, three had IL-5, and seven had IL-10. The levels of IL-4 and IL-5 did not reach statistical significance as compared with controls. Lastly, in individuals receiving the prime–boost regimen, the mRNA response was amplified via PCR to verify the cytokine findings. In all those tested (6), HIV-specific cytokine mRNA was identified. No cytokine mRNA was detected from either the control group or those that received the protein boost only.
Comments
This study demonstrates response rate of cytokines in an attempt to correlate clinical protection from disease. CD4 T cells can be divided into Th1 and Th2, with Th1 controlling intracellular pathogens and Th2 controlling extracellular pathogens.
The number of subjects was low—only 29, with only six undergoing the PCR analysis of mRNA. Furthermore, no demographic information was given, which may make the applicability difficult, certainly in terms of HIV risk stratification. There was a different immunization schedule as compared with other studies, which may make the generalization of results difficult. There is no explanation given as to why an accelerated immunization schedule was used, completing the series within a month, rather then the usual 6–9 months.
The expression of cytokines is an important step prior to phase III efficacy trials. If able to induce the products of CTL, one can assume that this is adequate activation of this arm of the immune system. Future vaccine research will probably focus on both antibody response as well as activation of CTL. This holds the best promise for protection from HIV. Clearly further studies are necessary to answer this debate, now that safety has been established.
Conclusion
In conclusion, there have been many recent changes in the design of the HIV vaccine. Certainly past attempts to induce an antibody response to the envelope protein have fallen into question. Current knowledge is tending towards inducing both an antibody response as well as a T cell-mediated response. In order to induce the T cell arm of the immune system, the protein needs to be presented from a live cell. This has resulted in the development of the recombinant canarypox vaccine linked to the envelope protein of the CD4 receptor. Phase I and II trials have proven safety and tolerability. Clinical trials of these vaccines will eventually be able to determine protective efficacy for HIV.
References
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2
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13
Rosenberg ES, Billingsley JM, Caliendo A et al. Vigorous HIV-1-specific CD4+ T-cell responses associated with control of viraemia. Science 1997; 278: 1447–1450.
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Ogg GS, Jin X, Bonhoeffer S et al. Quantitation of HIV-1 specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998; 279: 2103–2106.
17
Jin X, Bauer DE, Tuttleton SE et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques J Exp Med 1999; 189: 991–998.
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