Organizers: Robert C. Gallo, University of Maryland School of Medicine, John M. Coffin, Tufts University,
Mila Pollock, Cold Spring Harbor Laboratory, & Bruce D. Walker, The Ragon Institute of MGH, MIT & Harvard
Historical Narrative and Contributions to HIV Research
Warner C. Greene, MD, PhD
Working at the National Cancer Institute, Tom Waldmann, Warren Leonard and I described a monoclonal antibody, anti-Tac, that recognized the receptor for interleukin 2 (T-cell growth factor) (Leonard, WJ et al., Nature 1982) and used this antibody to clone cDNAs encoding the alpha-chain of the trimeric high-affinity IL-2 receptor (Leonard, WJ. et al., Nature 1984). We then described the deregulated expression of IL-2R-alpha mRNA in HTLV-I-infected leukemic T-cells (Kronke, M. et al., Science 1985), the induction of IL-2R-alpha gene expression by the HTLV-I Tax oncoprotein (Wano, Y. et al., PNAS 1988), the common activation of IL-2R-alpha and the HIV LTR by NF-kappa B (Bohnlein E et al., Cell, 1988, Molitor, JA et al., PNAS 1990)), autoregulation of NF-kappa B by I-kappa B-alpha involving its initial complete degradation during cellular stimulation followed by NF-kappa B-induced resynthesis (Sun, SC et al., Science 1993) and that nuclear NF-kappa B is regulated by intranucelar acetylation of its RelA subunit (Chen et al., Science, 2001). Other studies showed that HIV Nef was not a negative factor but instead a positive factor enhancing viral replication in primary CD4 T cells (Hammes SR et al., PNAS 1989; Miller, MD, et al., J. Virol. 1995), that HIV Vpr can induce nuclear membrane blebbing and rupture (deNoronha C et al., Science 2001), that HIV Vif acts by degrading and reducing the synthesis of APOBEC3G (Stopak K. et al., Mol. Cell, 2003), that Alu retroelements form the natural targets of APOBEC3G (Chiu YL et al., PNAS, 2006) and that the long elusive mouse Rfv3 restriction factor for the Friend Leukemia Virus is encoded by the mouse APOBEC3 gene.
More recently, we have focused on a fundamental question in HIV biology, namely how CD4 T-cells die. Surprisingly, most cells die due to an innate immune response against the virus rather than a toxic effect of the virus itself. Most dying CD4 T-cells correspond to quiescent bystander CD4 T-lymphocytes that undergo abortive viral infection arresting during the reverse transcription step of the viral life cycle (Doitsh et al., Cell 2010). The cells die as a consequence of IFI16-mediated sensing of this cytosolic viral DNA (Monroe et al., Science 2014) triggering inflammasome assembly, caspase-1 activation and pyroptosis, a highly inflammatory form of programmed cell death (Doitsh et al., Nature 2014). Although designed to protect the host from spread of infection, these host responses establish a vicious cycle, where dying CD4 T-cells release inflammatory signals that attract more cells to die Cell-to-cell transmission of HIV-1 is required to trigger pyroptosis indicating that infected cells rather than free virions form the major killing units (Galloway et al., Cell Reports, 2015). Surprisingly, blood CD4 T-cells are highly resistant to pyroptosis unless first mixed with cells from lymphoid tissue (Munoz Arias et al., Cell Host & Microbe, 2015). These studies reveal how CD4 T-cells gain and lose sensitivity to the pyroptotic pathway as they circulate in and out of lymphoid tissues and perhaps explain why this form of cell death was not detected earlier.
AZT and the Cornerstone of Antiretroviral Therapy for Patients with AIDS
Samuel Broder, MD
We are approaching the thirtieth anniversary of the FDA approval of AZT (March 19, 1987). This was the first targeted therapy against HIV-1, the pathogenic retrovirus responsible for the Acquired Immunodeficiency Syndrome (AIDS) that was approved by the Agency. AIDS was then a terrifying and lethal disease. Since that time, AIDS has gone from being an “inherently untreatable” infectious agent to one eminently susceptible to an astonishing range of therapies, mostly in the form of small molecules. Starting in the mid-1980s, my group at the National Cancer Institute played a unique and foundational role in the discovery and development of chain-terminating nucleosides in the therapy of HIV-1/AIDS. We initially focused on AZT and related congeners in the dideoxynucleoside family of nucleoside reverse transcriptase inhibitors (NRTIs), taking them from laboratory to the clinic and back again in a continuous motion. This first required crucial proof of both activity against HIV-1 per se and a sparing of normal helper-inducer T cells, especially so since this was the first-ever use of these drugs in human beings. Starting with AZT and followed by other dideoxynucleosides, these drugs proved that HIV-1 infection is treatable. Such proof provided momentum for new therapies from many sources, directed at a range of retroviral targets, and in the bargain, eventually did so at a pace that has rarely if ever been matched in modern drug development.
Antiretroviral therapy is responsible for a substantial decrease in the death rate due to HIV-1/AIDS, transforming it from a rapidly lethal disease into a chronic manageable condition. There is also evidence that such therapies can reduce vertical transmission in pregnancy and diminish infectiousness for sexual transmission. All of these developments have special implications within the classic boundaries of public health around the world, but at the same time, in certain regions might also affect a cycle of economic and civil instability in which HIV-1/AIDS is both cause and consequence. Certainly many challenges remain, including 1.) lifelong duration of therapy; 2.) full implementation of pre-exposure prophylaxis (PrEP); 3.) care-coordination and case-management in substance-using patients; 4.) additional longer-term follow-up for sexual activity without condoms in serodifferent couples when the HIV-positive partner is given suppressive anti-retroviral treatment; 5.) cardiometabolic side effects or other toxicities of long-term therapy; 6.) emergence of drug-resistance and viral genetic diversity (non-B subtypes); 7.) risk of new cross-species transmissions from established retroviral reservoirs in apes and Old World monkeys; and 8.) continued pace of new HIV-1 infections in many parts of the world. Nevertheless, perhaps one may now credibly ask whether a true cure for HIV-1/AIDS is in the offing. For example, might it be possible to achieve in vivo excision of HIV-1 DNA by gene editing, as recently published work has suggested, using a short version of Cas9 endonuclease together with a multiplex of guide RNAs (gRNAs) and delivery by an rAAV9 vector or a related technology?
Please share your thoughts about the meeting and the field.
Contact Mila Pollock at email@example.com
Flossie Wong-Staal, PhD
Congratulations on an outstanding organization of the HIV History and Future meeting. I really enjoyed the personal stories and collegial discussions in and out of the auditorium. The impact and historical significance of the meeting were momentous. Thank you for making me a part of it.
Marty St. Clair, PhD
I was thrilled when John Coffin asked me to present at this historic meeting. I was unbelievably honored to be in the same room with the brightest and the best in HIV. This meeting was incredibly well organized and told an amazing story of research and medicine that has brought us to the situation we have today. I am so glad the presentations will be made available online. Everyone should have the opportunity to experience this meeting.
Bob Gallo, MD
[comment on the meeting]
The meeting was the best I have attended on HIV/AIDS for several reasons: the top quality of science, the unique aspect of bringing in the history which shows how a field developed and responded to the challenges as well as the basic science background which helped advance the field, such as knowledge of animal retrovirology like details of integration of the provirus so applicable to today's research problems, and finally the overall openness and warmth of the speakers and other participants fostered by the Cold Spring Harbor atmosphere and the presence of Jim Watson.
I had one regret: in the panel public discussion, I was asked how we could have done better. I neglected to emphasize my belief that past lessons of epidemic diseases seem to be lost after a few decades, and when AIDS came, the medical science community as a whole was not arguing favorably for research on potential epidemic viral diseases. I note that the laboratory research groups who contributed most in the earliest period became involved quite by chance. At the same time and even continuing today there are inadequate numbers of newly trained virologists and the future in this regard is also subject to chance. We need responsible, expert, available, connected virologists collectively covering every kind of virus and also willing to engage in training new generations on a permanent basis. For this reason, the late Reinhard Kurth of Germany, Billy Hall of Ireland and I created the Global Virus Network (GVN), which is off and running, but in need of modest continuous funding.
Harold Varmus, MD
I was pleased when the meeting’s organizers decided to devote the opening session to early work on the viruses we now call retroviruses, because that work is the foundation on which HIV’s history properly rests. For the scientific community I represented at the meeting, this is critically important. Support by NIH and others for wide-ranging studies of RNA tumor viruses of birds and rodents---especially in the 1960’s and 70’s, well before AIDS emerged and HIV was identified---remains a strong argument for investing in animal models of disease and other forms of basic research.
Many important and unusual features of retroviral replication are now known as a result of such investments. But the most famous is reverse transcription, a step performed by a viral enzyme, reverse transcriptase (RT). The discovery of RT in 1970 by Howard Temin and David Baltimore transformed thinking about biology, helped to create the biotechnology industry, and made possible much of the work done by our lab and others.
John Coffin covered that terrain admirably at the workshop, and it fell to me to talk about what is arguably the second-most astonishing property of retroviruses: the efficient, irreversible, covalent association of DNA copies of their RNA genomes with host chromosomes, forming a “provirus.” This idea, first proposed by Temin in the 1960’s, has now been documented in many ways. As my slide deck makes clear, I tried to explain why integration is so important to the general behavior of retroviruses, how it helped to reveal the genetic basis of human cancer, and why it remains a critical feature of ongoing efforts to treat and even cure infection by HIV.
Integration ensures the indefinite persistence of an infecting virus’s genome in the host cell as a provirus and allows the provirus to become subject to the host cell’s apparatus for gene expression. The events that join viral to cell DNA require a viral enzyme (the integrase) that is now a target for useful anti-retroviral drugs (reviewed elsewhere in the program). And (as I illustrated in some detail) integration has essential roles in the two dominant mechanisms by which retroviruses cause cancer: viral capture of normal host cell genes with oncogenic potential (forming viral oncogenes from proto-oncogenes) and direct activation of proto-oncogenes by proviral insertion. Indeed many of the genes now understood to be central to human carcinogenesis and used as targets for novel therapies were discovered in early work with the retroviruses of birds and non-human mammals, well before a human genome project and cancer genomics were envisioned, let alone clinically useful.
The persistence of proviruses in cells is a source of frustration for those attempting to cure people infected with HIV. I concluded my talk by describing some recent findings from Steve Hughes’ laboratory in the NCI intramural program, showing that cells with HIV proviruses in certain loci often form large subclones in infected individuals. (A gratifying personal aspect of this work: Steve led important work on avian proviruses in our laboratory at UCSF nearly forty years ago!) His findings are provocative, but their explanations are not yet in hand, showing that we still have a lot to learn about fundamental aspects of retrovirology.
NEH awards leading San Francisco institutions $315,000 to digitize AIDS archives
The Archives and Special Collections department of the University of California, San Francisco (UCSF) Library, in collaboration with the San Francisco Public Library (SFPL) and the Gay, Lesbian, Bisexual, Transgender (GLBT) Historical Society, has been awarded a $315,000 implementation grant from the National Endowment for the Humanities. The collaborating institutions will digitize about 127,000 pages from 49 archival collections related to the early days of the AIDS epidemic in the San Francisco Bay Area and make them widely accessible to the public online. In the process, collections whose components had been placed in different archives for various reasons will be digitally reunited, facilitating access for researchers outside the Bay Area. The 24-month project, “The San Francisco Bay Area’s Response to the AIDS Epidemic: Digitizing, Reuniting, and Providing Universal Access to Historical AIDS Records” will commence on July 1, 2017.
Jon Cohen - Science Magazine reporter
In the article, At gathering of HIV/AIDS pioneers, raw memories mix with current conflicts, Jon Cohen wrote:
There are histories written by activists, relatives of people who died from AIDS, and denialists who did not believe in the “HIV/AIDS hypothesis.” There is the history that was told in PowerPoint presentations and barroom gabfests here at CSHL this autumn in the autumn of the careers of many pioneers, whose conflicts with each other long have been eclipsed by their collective accomplishment and their continued efforts to make HIV, once and for all, a thing of the past.
And there is the history written by future historians, who, Harden stressed, always get the last word.
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