When that day comes, Promega hopes to have played a supporting role.

The Need

HIV (human immunodeficiency virus) results in an intractable infection that is not only asymptomatic in many people, but also without a cure. Infection with HIV frequently results in acquired immunodeficiency syndrome, AIDS, which is characterized by a variety of secondary infections that can prove lethal. There are an estimated 39.5 million living with HIV/AIDS worldwide, 2.6 million more than in 2004 and twice the number in 1995. During 2006, an estimated 4.3 million new infections occurred, including 530,000 children. 2.9 million people died of AIDS-related illnesses in 2006; deaths worldwide are on the increase. Worldwide, most people living with HIV are unaware that they are infected (1).

The impact of HIV/AIDS worldwide varies by region. Sub-Saharan Africa has been hardest hit and is home to almost two-thirds (62.5%) of people living with HIV/AIDS, 24.7 million people. In Latin America and the Caribbean an estimated 2 million people are believed to be living with HIV/AIDS, 167,000 of whom were newly infected in 2006. Eastern Europe and Central Asia have an estimated 1.7 million people living with HIV/AIDS, representing the fastest growing HIV/AIDS epidemic worldwide, and one that is heavily concentrated among young people. South-East and East Asia have an estimated 8.6 million people living with HIV/AIDS; India and China have the highest new infection rates in this region. In the United States there are 1.2 million people living with HIV/AIDS; 42-59% are not getting treatment and 25% are unaware that they are infected (1).

The Commitment to Find New Therapies

There are currently drugs used in HAART (highly active antiretroviral therapy) that are successfully keeping HIV/AIDS individuals alive. But these persons are not free of the virus; they are not cured. For those on HAART, the virus becomes sequestered in tissues, in resting CD4+ T cells. If a patient stops taking HAART, viral blood levels rise.

No viral illness in the history of mankind has been eliminated from the population without the use of a vaccine. Smallpox, measles, mumps, polio...all have been controlled or eradicated by vaccination. However, vaccination holds no promise for the 39.5 million persons already infected and living with HIV/AIDS today. A cure for those already infected will require a magic bullet, a therapy that completely eliminates the virus from their systems.

Due to the unique geographic, economic and cultural issues involved in this worldwide epidemic, achieving a cure for the "final HIV patient" will require a multifactorial effort. The good news is that fascinating and promising research is on going today.

Recent Developments

Some recent developments in HIV research feature new uses of current therapeutics, such as viral excision using antiretroviral drugs (2) and prophylactic antiretroviral therapy (3). In addition, scientists are examining means of flushing HIV from T cells (4) and immunomodulation to stimulate CD8+ T cells to mimic a unique form found in persons known as HIV controllers; these unique T cells are a potential source of viral elimination (5). HIV controllers (HIC) were also noted to have lower CTLA-4 expression than non-HIC infected persons, thought to signal another pathway of HIV-related immune dysfunction (6). Other research is aimed at developing microbicides for vaginal application, as a preventative therapy (7, 8). Use the links under "HIV Research Today" on the right to view summaries of these research papers. Click on "More HIV Citations" to browse through a larger selection of recent papers.

References

1. Henry J. Kaiser Family Foundation "HIV/AIDS Policy Fact Sheet", June-July 2007; www.kff.org 
2. Sarkar, I. et al. (2007) HIV-1 proviral DNA excision using an evolved recombinase. Science 316, 1912-15.
3. Cohen, M. et al. (2007) Narrative review: Antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann. Intern. Med. 146, 591-601.
4. Lehrman, G. et al. (2005) Depletion of latent HIV-1 infection in vivo: A proof-of-concept study. Lancet, 366, 549-55.
5. Sáez-Cirion, A. et al. (2006) HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc. Natl. Acad. Sci. USA 104, 6776-81.
6. Kaufmann, D. et al. (2007) Upregulation of CTLA-4b HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nature Immunol. 8, 1246-54.
 
7. Stoddard, E. et al. (2007) gp340 expressed on human genitalia binds HIV-1 envelope protein and facilitates viral transmission. J. Immunol. 179, 3126-32.
8. Cole, A.L. et al. (2006) HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of gp41. J. Immunol. 176, 6900-05.

Viral Excision Using Antiretroviral Drugs

To achieve the goal of an HIV cure, the ideal might seem a pill that when taken, would remove virus from it's hiding place in CD4+ T cells. Current drug therapy, HAART (highly active antiretroviral therapy), targets the viral reverse transcriptase, protease and virus-host fusion mechanisms, and has resulted in longer lives and HIV-1 infection becoming a chronic, rather than fatal illness. But current therapies only suppress the virus, and new strains of HIV-1 are emerging that are resistant to current drug therapies. Sarkar et al. developed an evolved recombinase that specifically targeted an HIV-1 LTR and exised the integrated HIV proviral DNA from the genome of infected cells.

Citation: Sarkar, I., Hauber, I., Hauber, J. and Buchholz, F. (2007) HIV-1 proviral DNA excision using an evolved recombinase. Science, 316, 1912–15.

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Prophylactic Antiretroviral Therapy

Antiretroviral therapy holds promise in preventing the transmission of HIV. Emergency antiretroviral therapy is the standard of care after occupational exposures to fluids or tissues infected with HIV. And recently antiretroviral therapy has been widely used for nonoccupational HIV exposure; most countries have developed specific guidelines for implementing it. However, developing clinical trials to prove efficacy of such therapy for prophylaxis has only been possible in nonhuman primates, where protection has been shown with pre-exposure antiretroviral drugs. Several clinical trials are underway in nonhuman primates to evaluate the safety and efficacy of this approach. Experiments with rhesus macaques suggest that therapy must be offered within 72 hours of exposure and continued for 28 days. Other nonhuman primate studies have demonstrated protection from HIV infection with antiretroviral drugs prophylactically, and other trials are underway to evaluate the safety and efficacy of this approach. Cohen et al. review data on the use of antiretroviral drugs to prevent sexual transmisson of HIV and identify the challenges to improving this preventative technique.

Citation: Cohen, M.S., Gay, C., Kashuba, A.D.M., Blower, S. and Paxton, L. (2007) Narrative Review: Antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann. Intern. Med. 146, 591-601.

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Flushing HIV from T Cells

While some scientists are studying the use of antiretroviral therapy to excise HIV provirus from T cells (2), another route of investigation has looked at prodding latent HIV-1 from resting CD4+ T cells using histone deacetylase (HDAC1). This chromatin remodeling enzyme has been shown to maintain latency of the integrated HIV. Lehrman et al. examined whether valproic acid, an HDAC1 inhibitor, could deplete latently infected resting CD4+ T cells. They found that the frequency of infection of resting CD4+ T cells was stable before treatment in 4 volunteers. The volunteers were then treated with an intensified antiretroviral therapy plus valproic acid. After 3 months of therapy, the frequency of infection declined significantly in 3 of the 4 volunteers. The researchers saw a reduction of 75% in circulating HIV-infected resting CD4+ T cells and proposed this as a new approach to eventually clearing HIV from infected persons.

Citation: Lehrman, G., Hogue, I.B., Palmer, S, Jennings, C. Spina, C.A., Wiegan, A., Landay, A., Coombs, R.W., Richman, D.D., Mellors, J.W., Coffin, J.M., Bosch, R.J. and Margolis, D.M. (2005) Depletion of latent HIV-1 infection in vivo: A proof-of-concept study. Lancet 366, 549-555.

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Immunomodulation to Control Circulating HIV-1

There are exciting developments from those studying immunomodulation of HIV. Sáez-Cirion et al. studied an unusual group of HIV-1-infected individuals known as HIV controllers (HIC) that have a persistent but undetectable viral load in the absence of antiretroviral therapy. The circulating CD8+ T cells from these rare individuals are able to spontaneously control HIV-1 infection, which is very different from CD8+ T cells in non-HIC infected persons. The authors showed that HIC CD4+ T cells are susceptible to HIV-1 infection in vitro and that HIC-purified CD8+ T cells are able to efficiently control HIV-1 of autologous CD4+ T cells in vitro. Importantly, these experiments were conducted with ex vivo CD8+ T cells, in the absence of mitogens, showing that circulating HIC CD8+ T cells are prepared to control HIV-1 infection. The ability of these circulating CD8+ T cells from HIC persons to spontaneously control HIV-1 infection is in marked contrast to the actions of CD8+ T cells from other viremic persons. The hope is that further work could determine how to generate this unique CD8+ T cell type by vaccination or immune-based therapies.

Citation: Sáez-Cirión, A., Lacabaratz, C., Lambotte, O., Versmisse, P., Urrutia, A., Boufassa, F., Barre-Sinoussi F., Delfraissy, J-F., Sinet, M., Pancino, G. and Venet, A. (2007) HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc. Natl. Acad. Sci. USA. 104, 6776-81.

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Another immunomodulation report with potential therapeutic implications came from Kaufmann et al., where a molecule regulating CD4 function was studied. This regulatory protein, CTLA-4, was found to inhibit the activity of HIV-specific CD4 T cells. The authors showed that CTLA-4 was present in elevated levels on HIV-specific CD4 T cells, and that with disease progression, CTLA-4 expression increases and inhibits CD4 cell function. Interestingly, this inhibition appears to be reversible. In vitro tests blocking CTLA-4 resulted in improved function of HIV-specific CD4 cells, causing the authors to speculate about the use of CTLA-4 as a future target for therapeutic intervention.

Citation: Kaufmann, D.E., Kavanagh, G.G., Pereyra, F., Zaunders, J.J., Mackey, E.W., Miura, T., Palmer, S., Brochman, M., Rathod, A., Piechocka,-Trocha, A., Baker, B., Zhu, B., Le Gall, S., Waring, M.T., Ahern, R., Moss, K., Kelleher, A.D., Coffin, J.M., Freeman, G.J., Rosenbeg, E.S., Walker, B.D. (2007) Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nature Immunol. 8, 1246-54.

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Microbicides to Prevent Infection

Microbicides that can be used prior to sexual intercourse for blocking transmission of HIV-1 have been investigated and could become an important source of HIV protection, since heterosexual transmission is the principle means of HIV infection worldwide. Stoddard et al. studied submucosal CD4+ T cells and dendritic cells of the lower genital tract in women and identified a host protein, gp340 that is expressed on genital epithelium. The gp340 protein binds the HIV envelope by specific protein-protein interactions. This binding enables otherwise subinfectious amounts of virus to efficiently infect and allows the infection to occur over a longer period of time. The authors suggest that therapeutic agents aimed at blocking the interaction between the HIV-1 Env protein and gp340 could be developed for use as a potent and specific microbicide.

Citation: Stoddard, E., Cannon, G., Ni, H., Kariko, K., Capodici, J. Malamud, D., and Weissman, D. (2007) gp340 expressed on human genital epithelia binds HIV-1 envelope protein and facilitates viral transmission. J. Immunol. 179, 3126-32.

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Not only do microbicides hold great preventative potential by blocking HIV-1 transmission, but they are considered an important means of increasing compliance in many at-risk and uninfected populations. Another research effort looked at the defensins, an innate host defense with potential viral protection capabilities. In research published in the Journal of Immunology, Cole et al. used a nonhuman primate omega-defensin, partially expressed in humans, to synthesize retrocyclin, RC-100, which has antimicrobial and lectin-like properties. RC-100 inhibited infection of human primary CD4+ lymphocyctes by lab-adapted strains of HIV-1, as well as a number of clinical HIV-1 isolates. RC101, which differs from RC100 by a single amino acid (Arg-->Lys) substitution, was twice as active against HIV-1 isolates, and showed activity against HIV-1 in vaginal fluid, leading the authors to propose it's use as a vaginal microbicide to prevent sexually transmitted HIV-1.

Citation: Cole, A.L., Yang, O.O., Warren, A.D., Waring, A.J., Lehrer, R.I. and Cole, A.M. (2006) HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of gp41. J. Immunol. 176, 6900-05.

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