The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 34-35, July 2008

HIV/AIDS: Waiting for a cure

  • William T. Shearer, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: William T. Shearer, MD, PhD, Texas Children's Hospital, 6621 Fannin St (MC: FC330.01), Houston, TX 77030.

Departments of Pediatrics and Immunology, Baylor College of Medicine, and the Allergy and Immunology Service, Texas Children's Hospital, Houston, Tex

Received 20 May 2008; accepted 21 May 2008. published online 11 June 2008.

Article Outline

 

Designed to coincide with the early August 2008 XVII International AIDS Conference in Mexico City, this issue of the Journal of Allergy and Clinical Immunology is devoted to HIV/AIDS. The world, particularly the developing world, where the prevalence of this deadly infection is high, waits expectantly for deliverance from this plague. It is true that in the historically brief time of less than 3 decades, science and medicine have developed antiretroviral treatment regimens capable of preventing maternal-infant HIV transmission and extending the length and improving the quality of life for human subjects with behaviorally acquired infections. But the world expects more of its scientists and clinicians: it demands an AIDS vaccine that can prevent infection and possibly cure infection in those already infected. The resilience of the 9 HIV genes (see the cover picture) has thwarted the efforts of thousands of brilliant clinicians-investigators and billions of dollars of research support devoted to the creation of an AIDS vaccine.

For this thematic issue on AIDS, the Journal has selected 3 of the most eminent investigators in the world to review critical aspects of their research that will most certainly contribute to the cure of AIDS. Dr Anthony S. Fauci, along with his colleague, Dr Susan Moir, presents a review article on B-cell abnormalities in HIV infection that fills in the early void in knowledge of the role of B cells in HIV infection and promises the potential for new strategies for inducing antibodies to opportunistic organisms and HIV itself in the form of an effective vaccine.1 These authors point out another growing concern for HIV-infected patients: the development of B-cell malignancies in patients with long-standing HIV infection, a devastating fate for patients previously rescued by antiretroviral therapy. Harnessing the power of B cells for the treatment and prevention of HIV has been clearly outlined by Dr Fauci, the director of the National Institute of Allergy and Infectious Diseases.

In a remarkably lucid Molecular Mechanisms article on the critical issues in mucosal immunity for HIV vaccine development, Dr Barton F. Haynes, Director of the Duke Human Vaccine Institute and the Center for HIV/AIDS Vaccine Immunology, and Robin J. Shattock, St George's University of London, explain the clear failure of HIV vaccines, including that of the recombinant adenovirus type 5 HIV vaccine designed by Merck, in the STEP Phase IIb clinical trial.2 This candidate vaccine trial was halted in 2007 because of failure of efficacy in HIV high-risk participants and a trend toward enhanced acquisition of HIV infection in individuals with a high adenovirus 5 antibody level compared with the placebo control cohort.3 A second predisposing factor for enhanced acquisition of HIV was the lack of circumcision in men who received the vaccine.4 The explanation of these 2 factors has been the subject of numerous commentaries5, 6, 7 and of a town hall meeting convened by NIAID Director Anthony Fauci.8, 9, 10 Haynes and Shattock2 stress the need for an HIV vaccine to produce high levels of long-lived plasma cells (descendants of B cells) making broadly neutralizing antibodies that work at mucosal surfaces, the site of HIV entry. They describe the window of opportunity for such a vaccine to work as the time it takes for the HIV virus to begin to enter T-cell reservoirs, perhaps 25 days after initial infection and the point of no return thereafter.

Dr Robert F. Siciliano, Professor of Medicine at Johns Hopkins School of Medicine, has contributed a rostrum article on T-cell reservoirs of HIV.11 Shen and Siciliano11 suggest that the theoretic limits of the complete arrest of successive cycles of HIV replication have been reached with present antiretroviral medication regimens. However, eradication of HIV is not possible at this time because not all reservoirs of HIV have been identified. Thus at present, HIV viral replication can be suppressed with highly active antiretroviral therapy (HAART), but the virus cannot be completely eliminated.

In addition to these featured review articles on AIDS, this issue of the Journal also contains important original articles that touch on the importance of genetic inheritance and treatment effects in HIV infection. Singh et al12 provide compelling evidence for a protective effect of the innate immunity factor of the wild-type genotype mannose-binding lectin in 1037 HIV-infected children with a more favorable outcome than seen in the children who inherited the homozygous AA genotype and experience more rapid disease progression and central nervous system impairment. The effects were particularly noticeable in children younger 2 years, after which infectious complications blurred this distinction in older children born in the era before HAART. Mannose-binding lectin is known to interact with the HIV surface glycoprotein complex13 and dendritic cell–specific intercellular adhesion molecule–grabbing nonintegrin in a protective manner.14 This first and comprehensive study of the mannose-binding lectin pathway in pediatric HIV infection is another demonstration of the critical importance of fundamental biology and genetics in understanding the pathogenesis of the AIDS virus in human subjects. Along this same theme, Foster et al15 report on the asthma-sparing effect of HIV infection when unopposed CD4+ T-cell loss occurred in the pre-HAART era and the increasing asthma risk associated with HIV infection treated with HAART in the current era. This study of 2664 children born to HIV-infected mothers demonstrated a cumulative incidence of asthma of 33.5% in HIV-infected children treated with HAART and followed for up to 13.5 years compared with a cumulative incidence of 11.5% in HIV-infected children not treated with HAART. Assessing the change in percentage of CD4+ T cells before and after the initiation of asthma medications in HIV-infected children treated with HAART and those not treated with HAART showed a significant association between immunoreconstitution immune preservation and asthma. These authors conclude that the increased incidence of asthma in HIV-infected children treated with HAART is likely to be driven by the immunoreconstitution of CD4+ T cells and speculate that inflammatory cytokines and activated CD8+ T cells might also participate in this state of pulmonary hypersensitivity. These observations might be related, in part, to a similar observation of appearance of new forms of autoimmune disorders seen in HIV-infected adult patients treated with HAART16 and their common clustering of certain HLA class I alleles with the asthmatic HIV-infected children.17 In another treatment effect study, Li et al18 have made an important contribution to understanding the ebb and flow of thymic mature T-cell output and chronic T-cell activation in HIV-infected children and adolescents started on HAART therapy. Pre-HAART late-activated CD8+ T cells (CD3+CD8+CD45RA+CD27−CD11abright cells) were expanded in patients. Successful (measured by the decrease in HIV viral load) HAART therapy increased the percentage of naive T cells (CD3+CD4+CD45RA+CD27+CD28 and CD3+CD8+CD45RA+CD27+CD11adim cells), with a significant decrease in late-activated CD8+ T cells. T-cell excision circle values increased with increases in the naive CD4+ T cell percentage or decreased with increases in the CD8+ T-cell percentage, as did the normal Gaussian expansion of Vβ repertoire family increase or decrease. These longitudinal studies clearly demonstrate the homeostatic changes in thymic output with successful HAART therapy, which will be important as new forms of antiretroviral treatments are devised.

After a little more than a quarter century since the discovery of the AIDS virus and the knowledge we have quickly gathered on the molecular virology and immune pathogenesis of HIV infection, we pause to reflect on the power of modern science in grappling with the as yet elusive virus that leaves the world still waiting for its cure.

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I thank Dr Samuel B. Foster for a critical review of the editorial and Ms Carolyn Jackson for assistance with its preparation.

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References 

  1. Moir S, Fauci AS. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol. 2008;122:12–19
  2. Haynes BF, Shattock RJ. Critical issues in mucosal immunity for HIV-1 vaccine development. J Allergy Clin Immunol. 2008;122:3–9
  3. Sekaly RP. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development?. J Exp Med. 2008;205:7–12
  4. von Bubnoff A. The 15th Annual Meeting had its share of sobering news from clinical trials, but researchers also reported many exciting advances. IAVI Rep. 2008;12:1–5
  5. Cohen J. AIDS research. Did Merck's failed HIV vaccine cause harm?. Science. 2007;318:1048–1049
  6. Steinbrook R. One step forward, two steps back–will there ever be an AIDS vaccine?. N Engl J Med. 2007;357:2653–2655
  7. Cohen J. Retrovirus meeting. Back-to-basics push as HIV prevention struggles. Science. 2008;319:888
  8. Brown D. Vaccine failure is setback in AIDS fights: test subjects may have been put at risk of contracting AIDS. Washington Post; March 21, 2008;A1
  9. Rethinking is urged on a vaccine for AIDS. New York Times. March 26, 2008;A13
  10. Kaiser J. AIDS research. Review of vaccine failure prompts a return to basics. Science. 2008;320:30–31
  11. Shen L, Siciliano RF. Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection. J Allergy Clin Immunol. 2008;122:22–28
  12. Singh KK, Lieser A, Ruan PK, Fenton T, Spector SA. An age-dependent association of mannose-binding lectin-2 genetic variants on HIV-1–related disease in children. J Allergy Clin Immunol. 2008;122:173–180
  13. Ji X, Gewurz H, Spear GT. Mannose binding lectin (MBL) and HIV. Mol Immunol. 2005;42:145–152
  14. Spear GT, Zariffard MR, Xin J, Saifuddin M. Inhibition of DC-SIGN-mediated trans infection of T cells by mannose-binding lectin. Immunology. 2003;110:80–85
  15. Foster SB, McIntosh K, Thompson B, Lu M, Yin Y, Rich KC, et al. Increased incidence of asthma in HIV-infected children treated with highly active antiretroviral therapy in the National Institutes of Health Women and Infants Transmission Study. J Allergy Clin Immunol. 2008;122:159–165
  16. Reveille JD, Williams FM. Infection and musculoskeletal conditions: rheumatologic complications of HIV infection. Best Pract Res Clin Rheumatol. 2006;20:1159–1179
  17. Foster SB, Lu M, Thompson B, MacDonald KS, Winchester RJ, Rich KC, et al. HLA inheritance and asthma in HIV-infected children. Clin Immunol. 2008;127(Suppl):S46
  18. Yin L, Rodriguez CA, Wei H, Potter O, Caplan MJ, Goodenow MM, et al. Antiretroviral therapy corrects HIV-1–induced expansion of CD8+CD45RA+CD27−CD11abright activated T cells. J Allergy Clin Immunol. 2008;122:166–172

 Supported by National Institutes of Health (NIH) grants AI27551, AI069441, AI36211, HD41983, HD052102, RR0188, HL079533, HL72705, HL78522, and RAT003084A and contract AI41089; the Pediatric Research and Education Fund, Baylor College of Medicine; and the David Fund, Pediatrics AIDS Fund, and Immunology Research Fund, Texas Children's Hospital.

 Disclosure of potential conflict of interest: The author has declared that he has no conflict of interest.

PII: S0091-6749(08)00999-8

doi:10.1016/j.jaci.2008.05.029

Refers to erratum:

  • Correction

    The Journal of Allergy and Clinical Immunology August 2008 (Vol. 122, Issue 2, Page 253)

The Journal of Allergy and Clinical Immunology
Volume 122, Issue 1 , Pages 34-35, July 2008

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