Hyper-Virulent HIV—or Just Hype?
Abstract and Commentary
Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor, Stanford University School of Medicine Section Editor, HIV, is Associate Editor for Infectious Disease Alert
Synopsis: On February 11, 2005 the New York City Department of Health sent out a "Dear Colleague" letter reporting the case of a homosexual man who sustained primary infection with a 3-drug-class-resistant HIV-1 accompanied by rapid CD4+ T cell depletion and progression to AIDS.
Source: Torian L, et al. Primary 3-Drug-Class-Resistant HIV-1 Infection with Rapid CD4+ T cell Depletion and Progression to AIDS in a New York City Man who has Sex with Men. The City of New York Department of Health and Mental Hygiene. 2005; DOHMH Alert #7l.
In january 2005, a patient was diagnosed by markowitz and colleagues at Aaron Diamond Research Center with primary HIV infection with 3-drug-class-resistant HIV-1 (3DCR HIV), who had sustained rapid depletion of CD4+ lymphocyte count and rapid clinical progression to AIDS. The patient practiced unprotected insertive and receptive anal intercourse with multiple partners and reported crystal methamphetamine use. He last tested negative for HIV-1 in May 2003, had symptoms suggestive of acute retroviral syndrome in early November 2004, and tested positive for anti-HIV-1 antibodies on December 16, 2004.
By the time of presentation in January 2005, he had already sustained a 4 kg weight loss, had a CD4+ T-cell count of < 100/ mm3, and an elevated HIV RNA titer. Genotypic and phenotypic resistance testing performed by the south San Francisco company, ViroLogic, demonstrated broad cross-resistance to nucleoside analog reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (nnRTI), and protease inhibitors (PI). (The press release states the virus retained possible sensitivity to efavirenz, but it should be noted that this is a misleading artifact of phenotype assays, since despite in vitro phenotypic susceptibility of viruses to efavirenz, in the face of nevirapine or delavirdine associated mutations such as Y181C, patients will not respond in vivo to efavirenz.)
Comment by Dean Winslow, MD, FACP
This report generated a huge amount of attention in both the lay press and in the HIV treating community. While it has been known for some time that primary infection due to HIV-1 resistant virus can occur1 and resistance can persist in chronically infected treatment naïve patients,2,3 the occurrence of simultaneous resistance to all 3 classes of standard antiretroviral agents is most unusual. However, after the DOH press release, a number of scientists came forward reminding readers of previous reports of the occurrence of primary infection due to multi-drug-class-resistant HIV-1,4,5 including the CASCADE large European collaborative seroconverter cohort, where 0.5% of patients were infected with 3DCR virus6.
Much of the drama surrounding this case report concerns the perception that because of the reported patient’s rapid CD4+ T cell depletion and clinical progression, that a supervirus was now on the loose. Much of this anxiety has been fueled by the commonly held misperception on the part of many HIV-treating clinicians that HIV strains with drug resistance substitutions are less fit than wild type virus. Much of the blame for this misperception can be attributed to the aggressive marketing to clinicians by ViroLogic of the result of the drug-free control in their phenotype assay as a replication capacity or (RC) assay. In reality, since their assay relies on inserting an RT-PCR derived amplicon of the pol gene of a patient’s HIV (with only a few bases of the upstream gag region) into a defined infectious molecular clone, even wild type viruses often have replication capacities of less than 100% (range is reported to be from 25%-150%) of the whole infectious clone, when transfected into their cell line. (It was stated in discussion at the CROI meeting held the first week of March that the 3DCR isolate reported by Markowitz et al had an RC value of 136% (ie, within normal range.) Many of us who worked at the bench in the early days of HIV research in the 80s and early 90s, when whole virus was routinely isolated by cocultivation, were often impressed how cytolytic these CXCR4 (or dual tropic CXCR4/CCR5) isolates were in tissue culture. However, when we replicated the observed drug resistance substitutions by site-directed mutagenesis or created recombinant viruses similar to the ViroLogic construct, the viruses were often initially slow to grow after transfection. Follow-up work by individuals, including Carol Carter, demonstrated compensatory, increased efficiency of gag processing in highly NRTI-resistant virus that mapped to changes in the gag-pol p6/p7 region.7 In addition, Betsy Anton and Lee Bacheler at DuPont showed that non-cleavage site substitutions in gag p17 also nicely compensated for substitutions in the active site of protease, which produced the artifactual impaired replication capacity observed in recombinant virus or site-directed mutants which lacked these compensatory regions.8 Of course, rapid progression to AIDS following infection with HIV, is not a new phenomenon. Back in the pre-HAART era, this was not uncommonly observed and often associated with presumed biological cofactors in the host, such as advanced age, immunosuppression, and drug use as in the reported case.
While the case reported in New York is probably not that unusual, some important good may come from the associated publicity. This should include routine resistance testing of all patients’ HIV isolates prior to initiation of antiretroviral therapy, and renewed efforts by all of us in health care as well as the community to redouble efforts to prevent transmission of HIV.
References
- Little SJ, et al. Antiretroviral Drug Resistance Among Patients Recently Infected With HIV. N Engl J Med. 2002;347:385-394.
- Novak RM, et al. Prevalence of Antiretroviral Drug Resistance Mutations in Chronically HIV-Infected, Treatment-Naïve Patients: Implications For Routine Resistance Screening Before Initiation of Antiretroviral Therapy. CID. 2005;40:468-474.
- Grossman Z, et al. Drug-Resistant HIV Infection Among Drug-Naïve Patients in Israel. CID. 2005;40:294-302.
- Montaner J, et al. ProMED-mail. 20010810.1892.
- Pillay D, et al. ProMED-mail. 20050225.0604.
- Wensing AMJ, et al. The CATCH Study: Combined Analysis of Resistant HIV Transmission Over Time of Chronically and Acutely Infected Patients in Europe. 2nd IAS Conference on HIV Pathogenesis and Treatment. 2003; Paris, France.
- Zybarth G, et al. Domains Upstream of the Protease in HIV Gag-Pol May Contribute to Selection of Resistant Variants By Compensating For the Negative Effects of Mutations in PR. 4th Workshop on Viral Resistance. 1995; Annapolis, MD.
- Anton E, et al. Replicative Ability of HIV Variants With Substitutions in the Active Site of Protease is Dependent on Compensatory Mutations Outside the Active Site. 4th Conference on HIV Drug Resistance. 1995; Sardinia, Italy.
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