Nancy L. Haigwood (ONPRC) and R. Paul Johnson (YNPRC)

Improved therapies to treat HIV patients, as well as an effective vaccine to protect uninfected individuals from future HIV infection, are both urgent public health priorities. Important information has come from studying HIV infection and AIDS in humans over the last 30 years, as well as from studying nonhuman primate (NHP) models for AIDS.

HIV infects and kills millions globally. In 2017, about 36.9 million people worldwide were living with HIV, and about 940,000 have died of AIDS-related illnesses. Globally, there were about 1.8 million new cases of HIV, with about 180,000 new infections in children (Global HIV & AIDS statistics — 2018 fact sheet). In the United States, AIDS disproportionately affects Hispanics, African Americans, and other ethnic minorities (http://www.cdc.gov/hiv/basics/statistics.html).

One of the major issues with HIV, in contrast to viruses that infect their hosts for a few days or weeks, is that it establishes a persistent infection that has been so far impossible to eradicate in humans (with a single notable exception, see below). Combinations of antiretroviral medications can lengthen lives by keeping viral loads at or near undetectable levels in many HIV patients. However, many HIV-infected patients do not have access to antiretroviral medications or are not able to stay on treatment. In addition, these drugs are not curative and progression to AIDS resumes if drug treatment is interrupted. Thus treatment that is started as soon as infection is detected is now the recommended approach to limit disease progression and damage to immune cells (UCSF news article). Drug treatment in mothers prior to delivery of newborns has greatly reduced transmission from mother to child, but children born to HIV-infected mothers still have a high risk of contracting the infection during birth or via breastfeeding in areas of the world where drug therapy is not available.

African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIV), two of which have infected humans and generated HIV-1 and HIV-2. Chimpanzees are known to be the source of HIV-1 [1], and they, like humans, are variably susceptible to disease [2]. A few HIV patients have been found with genetic variations or other biological mechanisms that appear to naturally control the virus post-infection. These “elite controllers” are extremely uncommon, however, and scientists can only study them in limited ways.

For the last 30 years, the NPRCs have led the way by hosting research programs using NHP models for AIDS that have resulted in critical breakthroughs, as noted in the Key Publications listed below. All NPRCs have active NHP AIDS research programs serving researchers throughout the United States and impacting research progress worldwide. Genetically well-characterized NHPs used in controlled research and animal care settings at the NPRCs have informed researchers about early viral infection, viral escape from host immune responses, and potential vaccine targets. Asian monkeys, such as rhesus, cynomolgus and pig-tailed macaques have served as the flagship, lifesaving models for understanding the basics of infection routes, timing and doses that SIV requires to set up productive, lifelong infections mimicking HIV in humans and providing fundamental information on how SIV and HIV cause disease.

Some of the key lessons learned include knowledge that the immune systems in these animals are analogous to ours, which opens the door to exploring vaccines and immune-based therapies in NHPs. A lab-modified SIV incorporating parts of HIV– simian human immunodeficiency virus (SHIV) – has proved to be a useful tool in the NHP researchers’ arsenal to develop today’s medicines to treat HIV, as well as in the hunt for a vaccine [3]. NPRC researchers have also contributed to the development of using antiviral drugs for pre-exposure and post-exposure prophylaxis, vaginal microbicides [4] to help prevent sexual transmission of HIV to women [5] and safer medicines to prevent HIV transmission from a pregnant woman to her fetus or newborn [6].

There is still a great need for research into more effective treatments for people who already have HIV. Millions of people around the world cannot afford to take antiretroviral drugs to treat HIV, and many countries do not have the resources to provide their citizens with these medicines. Ultimately, researchers aim to find treatments that will result in long-term suppression of HIV infection or a cure for AIDS. Studies in NHP and other animal models have played an important role in showing promising leads in this effort [7]. The single report of an HIV-infected patient who has remained off antiretroviral medication and apparently free of HIV after undergoing a bone marrow transplant to treat leukemia (the Berlin patient—(#15 Hutter NEJM 2009)) has prompted a renaissance of efforts to develop strategies to eradicate HIV and SIV from infected individuals, and testing in NHP models will undoubtedly play a major role in moving these studies forward to human clinical trials.

The ultimate goal of HIV vaccination is to stimulate immunity that will either prevent the virus from getting established or will help to control it, so that drug therapy is not required [8]. Many candidate HIV vaccines have been tested in preclinical NHP models, and the most promising are moving into human clinical trials. The challenge is to find a vaccine that is safe and effective against all strains of the virus. This is critically important because the virus often mutates as it jumps from person to person. HIV not only incorporates itself into the hosts’ genetic material and hijacks their immune system, but viral mutations from infections of a previous host may allow it to overcome drug therapies and immune responses that have previously controlled it. One new approach to vaccination—and possibly treatment-- includes using powerful human HIV-specific monoclonal antibodies [9] or other protective artificial proteins [10] as “gene therapy.” These proteins can be given “passively” or expressed continuously in nonhuman primates and have been shown to prevent infection when these animals are exposed to SHIV or SIV. Human trials of monoclonal antibodies have been proposed [11] and are underway in the setting of pre-exposure and post-exposure [12], based on the success of some of these antibodies in preventing infection in NHP models [13, 14].

Access to better and safer medicines, a prophylactic vaccine, and continuing preventive strategies are all still urgently needed to achieve the goal of and AIDS-free generation. Strategies known to reduce transmission include educating people about condom use, avoiding contaminated needles, using pre-exposure prophylaxis (PrEP), and treating HIV-infected mothers with drugs during labor to limit virus exposure [11]. With effective deployment of prevention and treatment strategies, many experts in the field believe it will be possible to control and stop the AIDS pandemic.

Article References

1. Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, et al.
Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes.
Nature. 1999;397(6718):436-41. doi: 10.1038/17130. PubMed PMID: 9989410.

2. Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, et al.
Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz.
Nature. 2009;460(7254):515-9. Epub 2009/07/25. doi: nature08200 [pii]10.1038/nature08200. PubMed PMID: 19626114.

3. Hessell AJ, Haigwood NL.
Animal models in HIV-1 protection and therapy.
Curr Opin HIV AIDS. 2015. doi: 10.1097/COH.0000000000000152. PubMed PMID: 25730345.

4. Veazey RS.
Microbicide safety/efficacy studies in animals: macaques and small animal models.
Curr Opin HIV AIDS. 2008;3(5):567-73. Epub 2009/04/18. doi: 10.1097/COH.0b013e32830891bb01222929-200809000-00008 [pii]. PubMed PMID: 19373023.

5. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
Science. 2010;329(5996):1168-74. doi: 10.1126/science.1193748. PubMed PMID: 20643915; PubMed Central PMCID: PMCPMC3001187.

6. Van Rompay KK, Berardi CJ, Aguirre NL, Bischofberger N, Lietman PS, Pedersen NC, et al.
Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection.
AIDS. 1998;12(9):F79-83. PubMed PMID: 9662190.

7. Hansen SG, Piatak M, Jr., Ventura AB, Hughes CM, Gilbride RM, Ford JC, et al.
Immune clearance of highly pathogenic SIV infection.
Nature. 2013;502(7469):100-4. Epub 2013/09/13. doi: 10.1038/nature12519. PubMed PMID: 24025770; PubMed Central PMCID: PMC3849456.

8. Picker LJ, Hansen SG, Lifson JD.
New paradigms for HIV/AIDS vaccine development.
Annu Rev Med. 2012;63:95-111. Epub 2011/09/29. doi: 10.1146/annurev-med-042010-085643. PubMed PMID: 21942424.

9. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, et al.
Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys.
Nat Med. 2009. Epub 2009/05/19. doi: nm.1967 [pii]10.1038/nm.1967. PubMed PMID: 19448633.

10. Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, Chiang JJ, et al.
AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.
Nature. 2015;519(7541):87-91. doi: 10.1038/nature14264. PubMed PMID: 25707797; PubMed Central PMCID: PMCPMC4352131.

11. Voronin Y, Mofenson LM, Cunningham CK, Fowler MG, Kaleebu P, McFarland EJ, et al.
HIV monoclonal antibodies: a new opportunity to further reduce mother-to-child HIV transmission.
PLoS Med. 2014;11(4):e1001616. doi: 10.1371/journal.pmed.1001616. PubMed PMID: 24714363; PubMed Central PMCID: PMCPMC3979646.

12. Ledgerwood JE, Coates EE, Yamshchikov G, Saunders JG, Holman L, Enama ME, et al.
Safety, Pharmacokinetics, and Neutralization of the Broadly Neutralizing HIV-1 Human Monoclonal Antibody VRC01 in Healthy Adults.
Clin Exp Immunol. 2015. doi: 10.1111/cei.12692. PubMed PMID: 26332605.

13. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, et al.
Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys.
Nature. 2013;503(7475):224-8. doi: 10.1038/nature12744. PubMed PMID: 24172905; PubMed Central PMCID: PMCPMC4017780.

14. Shingai M, Nishimura Y, Klein F, Mouquet H, Donau OK, Plishka R, et al.
Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia.
Nature. 2013;503(7475):277-80. doi: 10.1038/nature12746. PubMed PMID: 24172896; PubMed Central PMCID: PMCPMC4133787.

15. Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, et al. (2009)
Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation.
The New England journal of medicine 360: 692–698. doi: 10.1056/nejmoa0802905. PubMed PMID: 19213682

Recent NPRC Publications

There are currently 820 publications available for HIV, SIV, SHIV, and AIDS.

2018

Aid M, Dupuy FP, Moysi E, Moir S, Haddad EK, Estes JD, Sekaly RP, Petrovas C, Ribeiro SP
Follicular CD4 T Helper Cells As a Major HIV Reservoir Compartment: A Molecular Perspective.
Front Immunol 2018 ; 9(): 895.

Amanna IJ, Slifka MK
Successful Vaccines.
Curr. Top. Microbiol. Immunol. 2018 Jul; (): .

Amedee AM, Phillips B, Jensen K, Robichaux S, Lacour N, Burke M, Piatak M, Lifson JD, Kozlowski PA, Van Rompay KKA, De Paris K
Early Sites of Virus Replication After Oral SIVmac251 Infection of Infant Macaques: Implications for Pathogenesis.
AIDS Res. Hum. Retroviruses 2018 Jan; (): .

Balasubramanian P, Williams C, Shapiro MB, Sinangil F, Higgins K, Nádas A, Totrov M, Kong XP, Fiore-Gartland AJ, Haigwood NL, Zolla-Pazner S, Hioe CE
Functional Antibody Response Against V1V2 and V3 of HIV gp120 in the VAX003 and VAX004 Vaccine Trials.
Sci Rep 2018 Jan; 8(1): 542.

Banerjee P, Ries M, Janaka SK, Grandea AG, Wiseman R, O'Connor DH, Golos TG, Evans DT
Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque.
Journal of immunology (Baltimore, Md. : 1950) 2018 Nov; 201(9): 2776-2786.

More...

Other Key HIV/AIDS Publications (NPRC and Non-NPRC)

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