By Jordana Lenon
Dec. 1, 2019
Nearly 38 million people are living with HIV, according to the World Health Organization.
The key word in that sentence is living.
While AIDS is still lethal for those who cannot afford or are otherwise not receiving life-saving medicines, a rapidly growing number of people are finally able to describe their illness as a chronic condition versus a death sentence. As anyone with a life-threatening disease will tell you, taking handfuls of pills every day, dealing with side effects, the fear of opportunistic infections, rising healthcare costs, plus endless doctors’ visits and lab work is no picnic. But it’s better than the alternative.
The NIH World AIDS Statement last year highlighted this new era of living with AIDS. The statement mentioned the monkeys — the same monkeys our scientists at the WNPRC and collaborators are studying to advance new therapies and find a cure. A functional cure for HIV is no longer a fantasy. The NIH statement even included a twist on the classic AIDS red ribbon design by depicting it artistically as broadly neutralizing antibodies. These bNAbs, as they are called, are now in clinical trials.
Earlier this year, one WNPRC monkey was able to control the virus for three years after a single dose of viral vectors expressing three different bNAbs in a study performed by University of Miami scientists collaborating with the WNPRC. Gene editing methods such as CRISPR Cas9 also bring new ideas for therapies into sharper focus.
HIV scientists, including those at the WNPRC, have spent their careers seeking major preclinical advances such as these. Without three decades of basic research aimed at understanding the shape-shifting, complex and insidious AIDS virus in humans, as well as in rhesus macaques, whose immune systems are analogous to humans, we would not be where we are today.
The WNPRC AIDS research and vaccine development program, based at the UW–Madison AIDS Vaccine Research Laboratory for the past 15 years, has never been stronger according to WNPRC Associate Director of Research Services David Evans. One-third of the WNPRC total research portfolio is HIV/AIDS related grants, Evans shared in an October presentation at the center. He said this translates to current annual funding of $5.6 million, 16 investigators, and many more monkeys sticking around after test vaccine treatments due to the more effective therapies being researched.
AIDS research priorities today, according to Evans, are reducing the incidence of HIV/AIDS globally, developing “next generation” or novel therapies, focusing more on research toward a cure, and seeking a better understanding of the pathogenesis of co-infections and co-morbidities such as tuberculosis and Zika. As always, basic research, education and training remain priorities. Finally, he added, WNPRC scientists are committed to eliminating health disparities among people with HIV. These are the substandard health outcomes borne by economically, socially or other disadvantaged populations when compared to those who have better healthcare access and more treatment options available.
At UW-Madison, Primate Center scientists working on HIV research projects in addition to Evans include David O’Connor, Shelby O’Connor, Matthew Reynolds, Igor Slukvin and Ted Golos. Dave O’Connor, Reynolds and Evans began their research training at the WNPRC under HIV scientist David Watkins, then in the UW–Madison School of Medicine and Public Health’s Department of Pathology and Laboratory Medicine. Shelby O’Connor trained under Shigeki Miyamoto in the Department of Cell and Molecular Biology. Slukvin trained under Golos and pioneered along with James Thomson derivations of various blood lineages from pluripotent stem cells. He now has many collaborative projects aimed at advancing cell and gene transplant therapies for HIV, kidney disease, blood cancers, and other diseases of the blood and immune system.
Some key studies funded by the National Institutes of Health–National Institute for Allergy and Infectious Diseases (NIH-NIAID) and supported by core WNPRC resources and expertise are listed here:
- David Evans: Fcgamma receptor-mediated suppression of immunodeficiency virus replication, KIR and MHC class immunogenetics in SIV infection.
- David O’Connor: High-throughput identification of common CD8+ T cell responses to SIV and M. tuberculosis in rhesus macaques, assessing the impact of acquired immunodeficiency on congenital Zika virus.
- Shelby O’Connor: Characterizing the therapeutic efficacy of CD8+ T cell responses induced by the IL-15 superagonist AJT-803, Effects of SIV/SIV on unconventional T cells in immunity to M. tuberculosis in pre-adolescents.
- Matthew Reynolds: Alloimmunization in a novel prophylactic vaccine for AIDS viruses.
- Igor Slukvin and Ted Golos: CCR5-mutation via CRISPR to develop a monkey model to facilitate the development of novel stem cell-based therapies for AIDS.
- Ron Desrosiers (University of Miami): Gamma-2 herpesviruses as vaccine receptors for AIDS, immunoglobulins delivered by AAV vector for the prevention of SIV infection.
- Michael Farzan (Scripps Research Institute): Preventing HIV-1 transmission with a novel entry inhibitor, eCD4-Ig. (This project is funded by the Bill and Melinda Gates Foundation.)
- Douglas Nixon: (George Washington University) BELIEVE: Bench to bedside enhanced lymphocyte infusions to engineer viral eradication.
- Pamela Skinner (University of Minnesota): Targeting virus-specific CAR T cells to lymphoid follicles to achieve durable HIV suppression.
- David Watkins (University of Miami): Functional significance of CTL escape.
- James Whitney: (Harvard) Viral dynamics of rebound and control following early treatment of HIV/SIV.
The shared expertise of these scientists and their lab teams resulted in several high impact papers in 2019, including these three:
- Sutton MS, Ellis-Connell A, Balgeman AJ, Barry G, Weiler AM, Hetzel SJ, Zhou Y, Lau-Kilby AW, Mason RD, Biris KK, Mascola JR, Sullivan NJ, Roederer M, Friedrich TC, O’Connor SL. CD8β depletion does not prevent control of viral replication or protection from challenge in macaques chronically infected with a live attenuated simian immunodeficiency virus.J Virol. 2019 May 15. [Epub ahead of print] (With WNPRC senior author Shelby O’Connor)
- Gardner MR, Fellinger CH, Kattenhorn LM, Davis-Gardner ME, Weber JA, Alfant B, Zhou AS, Prasad NR, Kondur HR, Newton WA, Weisgrau KL, Rakasz EG, Lifson JD, Gao G, Schultz-Darken N, Farzan M. AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges. Sci Transl Med. 2019 Jul 24;11(502). (With WNPRC SPI and Immunology Services)
- Martinez-Navio JM, Fuchs SP, Pantry SN, Lauer WA, Duggan NN, Keele BF, Rakasz EG, Gao G, Lifson JD, Desrosiers RC. Adeno-associated virus delivery of anti-HIV monoclonal antibodies can drive long-term virologic suppression. 2019 Feb 20. [Epub ahead of print] (With WNPRC Immunology Services and Animal Services)
Next up, Evans said, the center is supporting two new AIDS research projects: In the first, Igor Slukvin, collaborating with Matt Reynolds, plans to take peripheral blood SIV cytotoxic T lymphocytes (CTLs) from an infected macaque and reprogram them into iPSCs to capture their T-cell receptors (TCR). They will then edit the receptors’ genome to make them SIV-resistant, and subsequently differentiate the iPSCs back to SIV-resistant CTLs for adoptive immunotherapies. In the second project, Reynolds and Slukvin will explore hematopoietic stem cell transplantation through CCR5 gene editing. A donor bone marrow transplant with a rare mutation in the CCR5 gene was what essentially cured the Berlin patient of HIV when doctors used the transplant to treat both his leukemia and his AIDS.