Department of HIV/Thoracic Medicine, Department of Medicine and Department of Immunology and Molecular Pathology, The Royal Free Centre for HIV Medicine, Royal Free Campus, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Keywords: immune control, immune-based therapies, HIV, highly active antiretroviral therapy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In this review, I shall describe the attempts at translating the present understanding of the immune processes at play during the course of HIV-1 infection into new treatment strategies. HAART has provided an opportunity to attempt to recover or boost immune responses, which are instrumental in the control of viral replication, when the bulk of HIV replication is suppressed by antivirals and immune reconstitution is taking place.7,8
![]() |
Natural history of HIV-1 and the HAART revolution |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Since the early years of the pandemic, considerable efforts have been made to try to control the progressive, virally-induced decline in immune defences which characterizes HIV-1 infection. HIV replication is understood to drive the immunological abnormalities associated with the infection, in particular the profound depletion in CD4 cells.
If left untreated, HIV-1 infection leads to AIDS and death in the majority of patients over a period of several years. A very small proportion of infected patients the so-called long-term non-progressors (LTNPs) remain free of disease, with a stable high CD4 count. They are able to control viral replication to low levels in the absence of treatment and represent one of the paradigms of immune control of HIV.11
The initial efficacy of HAART was dramatic on both laboratory markers, such as viral replication and CD4 depletion, and opportunistic infections. Mortality and morbidity were decreased by about 70% when two nucleoside analogues and a protease inhibitor were used simultaneously.2,3 Immune responses against common pathogens were also restored, resulting in the possibility of discontinuing primary and secondary prophylaxes against some AIDS-defining infections.12 However, HIV-1-specific T cell immune responses were initially not recovered in late infection.12
![]() |
Absence of eradication and HAART toxicity |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The long-term use of the present components of HAART regimens is raising grounds for concern. Although the efficacy of initial HAART can last for at least 4 years and clinical experience shows that highly compliant patients can remain aviraemic for longer periods of time, there are serious doubts about the feasibility of managing HIV infection with the very prolonged and continuous use of anti-retroviral agents.4,5 Short-term lack of compliance jeopardizes antiviral efficacy. Resistance to antivirals, mitochondrial toxicity and lipodystrophy will all require the continuous development of new antiviral agents with different resistance and toxicity profiles with an emphasis on limiting the duration of drug exposure. Finally, costs and the absence of access to antiviral therapy for the majority of patients affected by HIV-1 make new and simplified treatment strategies a particular priority.
![]() |
Immune responses and HIV |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Although the CD4 cell count rebounds to lower levels than those measured pre-infection, during the phase of resolution of the acute phase, natural history shows a subsequent chronic CD4 cell decline in the absence of therapy. The erosion of immune function occurs in the presence of a detectable CTL response against the virus until the very late stage of the infection.20 This paradox has led to several hypotheses for the various mechanisms leading to the CTL dysfunction which allows the virus to escape immune responses.21 HIV-1 mutational escape from host cytolytic specificities in peripheral blood and impaired cytotoxicity in lymphoid tissue occur rapidly after acute infection.22,23 Defects in antigen presenting cells may also hinder CTL function through a lack of appropriate co-stimulation.24,25
The present consensus is that CD4 help is crucial for CTLs functional activity for viraemia control in HIV-1 infection as in other viral infections.26 Activated HIV-specific CD4 cells are understood to be the main target of the virus, starting at the earliest stages of infection, and to be progressively deleted in the absence of antiviral intervention.27 These responses have been reported at high frequencies in LTNPs.28 It is likely that, whenever detected during the chronic stage, HIV-specific CD4 and CD8 cells are unable to proliferate and are not fully functional in progressive HIV infection.2931
Although evidence for the role of CD8 cells, and in particular of CTLs to HIV-1 host defence, has been supported by several animal and human studies in PHI and LTNPs, using CD8 cell depletion and the correlation of gag CTLs with viraemia levels and clinical progression, other immune parameters are presently being revisited.28,32,33 These include the components of innate immunity, neutralizing antibodies and the CD8 cell non-cytolytic function.19,34,35
![]() |
HAART and immune responses |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In the seminal studies about HAART and immune reconstitution, HIV-1-specific responses were not restored in persons with advanced disease.12 However, antiviral treatment preserved CD4 HIV-specific responses when initiated at PHI and possibly also during the first 6 months of infection.36
Improvement in HIV cell-associated immunity with HAART has been described in some but not all of the later studies in early chronic infection or at high CD4 cells counts and low viral load and in some patients with a low pre-HAART nadir CD4 count.37,38 There are presently no comparative studies of immune reconstitution of HIV-specific responses with HAART across the various CD4 strata to assess at which stage of the infection proliferative responses might be best preserved. PHI and the first 6 months of infection are the exception.36
One of the drawbacks of chronic antiviral therapy is the decrease in HIV-specific responses, possibly through a low level or absence of antigenic stimulation.29,39 Therefore, the re-exposure of the immune system to viral antigens as a therapeutic intervention represents an attempt at the boosting of the CD4 and CD8 HIV-specific responses in HAART-treated patients in order to strengthen the immune control against the virus.40
![]() |
Modalities and aims of therapeutic vaccination |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The main aim of such an intervention in the HAART era is to attempt the partial, temporary or total control of viral replication after the discontinuation of antiviral therapy. If successful, this strategy should in turn decrease or stop the CD4 loss and potentially delay or stop clinical progression. In clinical terms, it might allow patients to discontinue their antiviral therapy for a given period of time with the added benefit of a drug-holiday, and cause a decrease in HAART-induced toxicity and costs. An optimistic aim for this type of strategy would be to transform patients into LTNPs, besides viral eradication which would be the most successful outcome. This paradigm may be more realistically entertained in the very early stages of infection, in particular in PHI.
The strengthening of immune responses through re-exposure to heterologous antigens could also be envisaged to enhance viral control in patients on HAART in order to decrease treatment failure. Lastly, for the patients who remain untreated, particularly when antiviral drugs are unavailable, a potential role for therapeutic vaccines would be to allow for the delay of HAART initiation.
Autologous vaccines or auto-vaccination
Some case reports and small studies of patients at the chronic stage of the infection have suggested the possibility of immune control of HIV viraemia after discontinuation of HAART. This was associated with an increase in CD4 HIV-specific cells after several treatment interruptions (STI) during chronic HAART.41 These observations have led to several studies of structured treatment interruption in order to evaluate the possibility of viral control and type of immune responses generated by this strategy during both chronic and acute infection.42,43
In chronic infection, a Swiss-Spanish, prospective study (SSITT) enrolled a cohort of 133 patients on long-term HAART who underwent several treatment interruptions followed by treatment re-initiation and subsequent discontinuation of antiviral therapy. Ninety patients completed the four cycles and stopped HAART at week 40.43 Twenty-three of the 79 patients who could be evaluated 12 weeks after stopping treatment had a viraemia level below 5000 copies/mL and were considered as responders. Although there were increases in HIV-specific CD8 cells during treatment interruptions, these did not prevent viraemia rebound.44 These results and others, which have shown the possibility of emergence of viral resistance, clinical progression and new infections in partners of previously aviraemic patients, have generated a cautious approach towards this form of intervention outside clinical trials.
When testing this strategy in very early infection, the most quoted cohort includes 14 patients treated with HAART during PHI.42 A substantial proportion of these patients continued to maintain viral loads below 5000 HIV copies/mL up to 3 years after one to four treatment interruptions.45 However, there is presently no controlled trial which allows firm conclusions to be drawn on the effect of such a strategy in very early infection. It is not known whether prolonged antiviral therapy without treatment interruptions might be able to achieve similar results through CD4 help rescue and the decrease in viral differentiation.36
In conclusion, this form of approach has been conducted with mixed success although there are some encouraging results in acute infection. Further evaluation is needed to better define the role of planned therapeutic interruption in the treatment of HIV infection and the potential for combining it with immunomodulatory strategies.43
Heterologous vaccines
Numerous new vaccine candidates. There are presently no licensed prophylactic or therapeutic vaccines against HIV. None of the therapeutic vaccine candidates has shown long-term efficacy on the viral set-point, CD4 count or disease progression in a randomized trial. However, in the past few years, there has been an explosion in the number of new vaccine candidates [recombinant proteins, synthetic peptides, HIV peptides or lipopeptides, viral or bacterial vectors expressing HIV antigen(s), DNA vaccines and virus-like particles]. They are about to be or have been piloted in more than 60 Phase I trials since the beginning of the epidemic. Several Phase II trials are ongoing, and one Phase III trial has been completed while another is ongoing.4648 Efforts have concentrated on devising vaccines which can produce neutralizing antibodies and stimulate cell-mediated immunity. However, because of the difficulty in generating antibodies capable of neutralizing primary HIV-1 isolates, there has been a recent emphasis on T cell responses.
One of the approaches shown to increase T cell responsiveness is a prime-boost strategy using a DNA prime followed by boosting with a viral vector.49 Among the numerous new vaccine candidates for use with this type of approach are several avipox-based vector vaccines with inserted HIV genes such as modified virus Ankara (MVA), NYVAC and fowlpox and a new replication-defective adenovirus 5-based vaccine.46
Although the vaccine effort has mostly been geared towards the creation of one or several prophylactic vaccines, some of the new compounds are also in the process of been tested in the therapeutic arena. These complement others which have been more extensively piloted in the pre-HAART period such as Remune (a gp120 depleted whole inactivated virus), envelope-based recombinant gp120 and gp160 compounds, a core-based p24 virus-like particle vaccine (p24-VLP vaccine), and DNA plasmid compounds.5054
Therapeutic vaccines in the pre-HAART era. Initial vaccine candidates have demonstrated their safety and immunogenicity in HIV-positive individuals. However, when used on their own, some have shown a limited ability to generate HIV-specific immunity or neutralizing antibodies and led to rather disappointing therapeutic benefits in terms of CD4 increase, viral load decrease or delay in disease progression.5557
However, the general antigenic overload in the absence of control of HIV replication by powerful antiviral treatment, the various CD4 counts and viraemia levels of vaccinees and biases introduced by the introduction of HAART in some of these studies have precluded firm conclusions from being drawn about their efficacy and best clinical and immunological settings for their use in the HAART era.5860 A review suggested that the best immunogenicity for gp120 (envelope)-based vaccines might be achieved in patients with a baseline CD4 count of more than 350 cells/mm3 and a low level of viraemia.55 In a recent study, the best predictor of efficacy for Remune was the baseline CD4 count.61
The HAART era. Studies in animal models have recently supported the rationale for testing the association of antiretroviral therapy and therapeutic immunization in both early and chronic infection.62,63
The availability of HAART and the present focus on the importance of HIV-specific T cell immunity in the immune control of HIV viraemia have targeted new vaccine compounds for their potential to elicit strong and broad cellular immune responses for therapeutic use.46,47
Several generations of the recombinant canarypox-based vector (ALVAC-HIV) with various inserted HIV genes have shown their safety and immunogenicity in humans and HIV-1-infected individuals.64 The ALVAC-HIV vCP 1452 was recently piloted in early HIV infection in association with rgp160 or Remune.65,66 ALVAC vCP 1433 has also been used in two French studies in association with HAART or HAART, lipopeptides and cycles of interleukin-2 (IL-2).67,68
Other vaccine candidates which are in the pipeline for therapeutic use include the protein-based env-tat-nef compound developed by GlaxoSmithKline and a DNA-based vaccine administered intradermally.49,69 The latter encompasses the entire sequence of the HIV genome with deletion in the integrase gene. It has shown extremely encouraging results in terms of viraemia control at the late stage of infection in the monkey model in association with structured treatment interruptions.
It remains to be shown whether the addition of immunostimulatory strategies to vaccines such as cytokines in association with DNA alone or in prime-boost strategies with viral vectors will lead to an increased efficacy as suggested by some animal models.63,70,71 IL-2 was administered after immunization with a canarypox vaccine (ALVAC-HIV vCP 1433) and lipopeptides in a recent trial with encouraging results in terms of the possibility of treatment interruption.68 The description of the effect of cell-based vaccines using autologous dendritic cells pulsed with a chemically inactivated HIV in early SIV infection also deserves further studies.72
![]() |
Conclusions |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2
.
Palella, F. J., Delaney, K. M., Moorman, A. C. et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. Outpatient Study Investigators. New England Journal of Medicine 338, 85360.
3 . Mocroft, A., Vella, S., Benfield, T. L. et al. (1998). Changing patterns of mortality across Europe in patients infected with HIV-1. Lancet 352, 172530.[CrossRef][ISI][Medline]
4
.
Walmsley, S., Bernstein, B., King, M. et al. (2002). Lopinavirritonavir versus nelfinavir for the initial treatment of HIV infection. New England Journal of Medicine 346, 203946.
5 . Carr, A. & Cooper, D. (2000). Adverse effects of antiretroviral drugs. Lancet 356, 142330.[CrossRef][ISI][Medline]
6 . Sachs, J. D. (2001). A new global commitment to disease control in Africa. Nature Medicine 7, 5213.[CrossRef][ISI][Medline]
7 . Semprowski, G. D. & Haynes, B. F. (2002). Immune reconstitution in patients with HIV infection. Annual Review of Medicine 53, 26984.[CrossRef][ISI][Medline]
8 . Kinloch-de Loes, S. & Autran, B. (2002). HIV-1 therapeutic vaccines. Journal of Infection 44, 1529.[CrossRef][ISI][Medline]
9 . Jaffe, H. W., Bregman, D. J. & Selik, R. M. (1983). Acquired immune deficiency syndrome in the United States: first 1000 cases. Journal of Infectious Diseases 148, 33945.[ISI][Medline]
10 . Pantaleo, G., Graziosi, C., Demarest, J. D. et al. (1993). HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362, 3559.[CrossRef][ISI][Medline]
11
.
Pantaleo, G., Menzo, S., Vaccarezza, M. et al. (1995). Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. New England Journal of Medicine 332, 20916.
12 . Autran, B., Carcelain, G., Li, T. S. et al. (1997). Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112116.
13
.
Ho, D. D. (1995). Time to hit HIV, early and hard. New England Journal of Medicine 333, 4501.
14
.
Wong, J. K., Hezareh, M., Gunthard, H. F. et al. (1997). Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 12915.
15
.
Zhang, I., Ramratnam, B., Tenner-Racz, K. et al. (1999). Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. New England Journal of Medicine 340, 160513.
16 . Cooper, D. A., Tindall, B., Wilson, E. J. et al. (1988). Characterization of T lymphocyte responses during primary infection with human immunodeficiency virus. Journal of Infectious Diseases 157, 188996.
17 . Wilson, J. D. K., Ogg, G. S., Allen, R. L. et al. (2000). Direct visualization of HIV-1 specific cytotoxic T lymphocytes during primary infection. AIDS 14, 22533.[CrossRef][ISI][Medline]
18 . Moore, J. P., Cao, Y., Ho, D. D. et al. (1994). Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. Journal of Virology 68, 514255.[Abstract]
19
.
Richman, D. D., Wrin, T., Little, S. J. et al. (2003). Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proceedings of the National Academy of Sciences, USA 100, 41449.
20
.
Goulder, P. J. R., Tang, Y., Brander, C. et al. (2000). Functionally inert HIV-specific cytotoxic lymphocytes do not play a major role in chronically infected adults and children. Journal of Experimental Medicine 192, 181932.
21
.
Lieberman, J., Shankar, P., Manjunath, N. et al. (2001). Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 98, 166777.
22 . Borrow, P., Lewicki, H., Wei, X. et al. (1997). Antiviral pressure exerted by HIV-1 specific cytotoxic T lymphocytes (CTLs) during primary HIV infection demonstrated by rapid selection of CTL escape virus. Nature Medicine 3, 20511.[ISI][Medline]
23 . Andersson, J., Kinloch, S., Sonnerborg, A. et al. (2002). Low levels of perforin expression in CD8+ T lymphocyte granules in lymphoid tissue during acute human immunodeficiency virus type 1 infection. Journal of Infectious Diseases 185, 13558.[CrossRef][ISI][Medline]
24 . Andrieu, J. M., Chassin, D., Desoutter, J. F. et al. (2001). Downregulation of major histocompatibility class I on human dendritic cells by HIV Nef impairs antigen presentation to HIV-specific CD8+ T lymphocytes. AIDS Research and Human Retroviruses 17, 136570.[CrossRef][ISI][Medline]
25 . Lore, K., Sonnerborg, A., Brostrom, C. et al. (2002). Accumulation of DC-SIGN+CD40+ dendritic cells with reduced CD80 and CD86 expression in lymphoid tissue during acute HIV-1 infection. AIDS 16, 68392.[CrossRef][ISI][Medline]
26
.
Kalams, S. A., Buchbinder, S. P., Rosenberg, E. S. et al. (1999). Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. Journal of Virology 73, 671520.
27 . Douek, D., Brenchley, J., Betts, M. R. et al. (2002). HIV preferentially infects HIV specific CD4+ T cells. Nature 417, 958.[CrossRef][ISI][Medline]
28
.
Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M. et al. (1997). Vigorous HIV-1 specific CD4+ T cell responses associated with viral control. Science 278, 144750.
29 . Pitcher, C. J., Quittner, C., Peterson, D. M. et al. (1999). HIV-1 specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nature Medicine 5, 51825.[CrossRef][ISI][Medline]
30 . Wilson, J. D., Imami, N., Watkins, A. et al. (2000). Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression of disease. Journal of Infectious Diseases 182, 7928.[CrossRef][ISI][Medline]
31 . Champagne, P., Ogg, G. S., King, A. S. et al. (2001). Skewed maturation of memory HIV specific CD8 T lymphocytes. Nature 410, 10611.[CrossRef][ISI][Medline]
32
.
Schmitz, J. E., Kuroda, M. J., Santra, S. et al. (1999). Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 85760.
33 . Riviere, Y., McChesney, M. B., Porrot, F. et al. (1995). Gag specific cytotoxic responses to HIV type 1 are associated with a decreased risk of progression to AIDS-related complex or AIDS. AIDS Research and Human Retroviruses 11, 9037.[ISI][Medline]
34 . Bonaparte, M. I. & Barker, E. (2003). Inability of natural killer cells to destroy autologous HIV-infected lymphocytes. AIDS 17, 48794.[CrossRef][ISI][Medline]
35 . Yang, O. O., Kalams, S. A., Trocha, A. et al. (1997). Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and non-cytolytic mechanisms. Journal of Virology 71, 31208.[Abstract]
36
.
Altfeld, M., Rosenberg, E. S., Shankarappa, R. et al. (2001). Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. Journal of Experimental Medicine 193, 16980.
37 . Al-Arthi, L., Siegel, J., Spritzler, J. et al. (2000). Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease. AIDS 14, 76170.[CrossRef][ISI][Medline]
38 . Plana, M., Garcia, F., Gallart, T. et al. (1998). Lack of T-cell proliferative response to HIV-1 antigens after 1 year of highly active antiretroviral treatment in early HIV-1 disease. Lancet 352, 11945.[ISI][Medline]
39
.
Ogg, G. S., Jin, X., Boonhoeffer, S. et al. (1999). Decay kinetics of human immunodeficiency virus effector cytotoxic T lymphocytes after combination antiretroviral therapy. Journal of Virology 73, 797800.
40
.
Autran, B. & Carcelain, G. (2000). Boosting immunity to HIVCan the virus help? Science 290, 9469.
41 . Ortiz, G. M., Nixon, D. F., Trkola, A. et al. (1999). HIV-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. Journal of Clinical Investigation 104, R138.[ISI][Medline]
42 . Rosenberg, E. S., Altfeld, M., Poon, S. H. et al. (2000). Immune control of HIV-1 after early treatment of acute infection. Nature 407, 5236.[CrossRef][ISI][Medline]
43
.
Fagard, C., Oxenius, A., Gunthard, H. et al. (2003). A prospective trial of structured treatment interruptions in human immunodeficiency virus infection. Archives of Internal Medicine 163, 12206.
44
.
Oxenius, A., Price, D. A., Gunthard, H. F. et al. (2002). Stimulation of HIV-1 specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection. Proceedings of the National Academy of Sciences, USA 99, 1374752.
45 . Walker, B. D., Allen, T., Altfeld, M. et al. (2003). Immune control and immune failure in HIV infection. In Program and Abstracts of the Tenth Conference on Retroviruses and Opportunistic Infections, Boston, USA, 2003. Abstract 164, p. 118. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
46 . Robinson, H. L. (2002). New hopes for an AIDS vaccine. Nature Reviews Immunology 2, 23950.[CrossRef][ISI][Medline]
47 . McMichael, A. J. & Hanke, T. (2003). HIV vaccines 19832003. Nature Medicine 9, 87480.[CrossRef][ISI][Medline]
48 . Barnett, S. W., Srivastava, I., Stamatatos, L. et al. (2003). HIV-1 vaccines that include novel envelope structures induce broad and potent anti-viral immune responses. Antiviral Therapy 8, Suppl. 1, S230.
49 . McConkey, S. J., Reece, W. H. H., Moorthy, V. S. et al. (2003). Enhanced T cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nature Medicine 9, 72935.[CrossRef][ISI][Medline]
50 . Trauger, R. J., Daigle, A. E., Giermakowska, W. et al. (1995). Safety and immunogenicity of a gp120 depleted, inactivated HIV-1 immunogen: results of a double blind, adjuvant controlled trial. Journal of Acquired Immune Deficiency Syndromes 10, S7482.
51 . Eron, J. J., Jr, Ashby, M. A., Giordano, M. F. et al. (1996). Randomized trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection. Lancet 348, 154751.[CrossRef][ISI][Medline]
52 . Sandstrom, E. & Wahren, B. (1999). Therapeutic immunization with recombinant gp160 in HIV-1 infection: a randomized double-blind placebo-controlled trial. Nordic VAC-04 Study Group. Lancet 353, 173542.[CrossRef][ISI][Medline]
53 . Peters, B. S., Cheingsong-Popov, R., Callow, D. et al. (1997). A pilot phase II study of the safety and immunogenicity of HIV p17/p24:VLP (p24-VLP) in asymptomatic HIV seropositive subjects. Journal of Infection 35, 2316.[ISI][Medline]
54 . MacGregor, R. R., Boyer, J. D., Ugen, K. E. et al. (1998). First human trial of DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. Journal of Infectious Diseases 178, 92100.[ISI][Medline]
55 . Schooley, R. T., Spino, C., Kuritzkes, D. et al. (2000). Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1 infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214. Journal of Infectious Diseases 182, 135764.[CrossRef][ISI][Medline]
56 . Smith, D., Gow, I., Colebunders, R. et al. (2001). Therapeutic vaccination (p24-VLP) of patients with advanced HIV-1 infection in the pre-HAART era does not alter CD4 cell decline. HIV Medicine 2, 2725.[CrossRef][Medline]
57 . MacGregor, R. R., Boyer, J. D., Ciccarelli, R. B. et al. (2000). Safety and immune responses to a DNA-based human immunodeficiency virus (HIV) type 1 env/rev vaccine in HIV infected recipients: follow-up data. Journal of Infectious Diseases 181, 406.[CrossRef][ISI][Medline]
58
.
McNeil, A. C., Shupert, W. L., Iyasere, C. A. et al. (2001). High level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation. Proceedings of the National Academy of Sciences, USA 98, 1387883.
59 . Hoff, R. & McNamara, J. (1999). Therapeutic vaccines for preventing AIDS: their use with HAART. Lancet 353, 17234.[CrossRef][ISI][Medline]
60
.
Kahn, J. O., Cheng, D. W., Mayer, K. et al. (2000). Evaluation of HIV-1 immunogen, an immunologic modifier, administered to patients infected with HIV having 300549 x 106/L CD4 cell counts: a randomized controlled trial. Journal of the American Medical Association 284, 2193202.
61 . Moss, R. B., Wallace, M. R., Steigbigel, R. T. et al. (2002). Predictors of HIV-specific lymphocyte proliferative immune responses induced by therapeutic vaccination. Clinical and Experimental Immunology 128, 35964.[CrossRef][ISI][Medline]
62 . Hel, Z., Venzon, D., Poudyaal, M. et al. (2000). Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques. Nature Medicine 6, 11406.[CrossRef][ISI][Medline]
63
.
Tryniscewska, E., Nacsa, J., Lewis, M. G. et al. (2002). Vaccination of macaques with long-standing SIVmac251 infection lowers the viral set point after cessation of antiretroviral therapy. Journal of Immunology 169, 534757.
64 . Tubiana, R., Gomart, E., Fleury, H. et al. (1997). Vaccine therapy in early HIV-1 infection using a recombinant canarypox virus expressing gp160MN (ALVAC-HIV): a double-blind controlled randomized study of safety and immunogenicity. AIDS 11, 81920.[ISI][Medline]
65
.
Jin, X., Ramanathan, M., Jr, Barsoum, S. et al. (2002). Safety and immunogenicity of ALVAC vCP1452 and recombinant gp160 in newly human immunodeficiency virus type 1-infected patients treated with prolonged highly active antiretroviral therapy. Journal of Virology 76, 220616.
66 . Goh, L. E., Perrin, L., Hoen, B. et al. (2001). Study protocol for the evaluation of the potential for durable viral suppression after quadruple HAART with or without HIV vaccination: the QUEST study. HIV Clinical Trials 2, 43844.[Medline]
67 . Carcelain, G., Tubiana, R., Legarff, M. et al. (2003). HIV recombinant canarypox vaccine boosts and broadens HIV-specific CD4 and CD8 T-cells in the VACCITER ANRS 094 therapeutic immunization clinical trial. Antiviral Therapy 8, Suppl. 1, S231.
68 . Levy, Y., Gahery-Segard, H., Durier, C. et al. (2003). Immunological and virological efficacy of ALVAC-VIH 1433 and HIV lipopeptides (Lipo-6T) combined with SC IL-2 in chronically HIV-infected patientsresults of the ANRS 093 randomized study. In Program and Abstracts of the Tenth Conference on Retroviruses and Opportunistic Infections, Boston, USA, 2003. Abstract 62, p. 79. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.
69 . Lisziewicz, J., Bakare, N. & Lori, F. (2003). Therapeutic vaccination for future management of HIV/AIDS. Vaccine 21, 6203.[CrossRef][ISI][Medline]
70
.
Barouch, D. H., Santra, S., Schmitz, J. E. et al. (2000). Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 48692.
71 . Weiner, D. B., Boyer, J., Kutzler, M. et al. (2003). Th1 plasmid cytokine enhancement of RNA optimized plasmid DNA vaccine potency in non-human primates suggests attainment of a critical milestone in DNA vaccine and immune therapy development. Antiviral Therapy 8, Suppl. 1, S229.
72 . Lu, W., Wu, X., Lu, Y. et al. (2003). Therapeutic dendritic cell vaccine for simian AIDS. Nature Medicine 9, 2732.[CrossRef][ISI][Medline]
|