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Multidrug-resistant, dual-tropic HIV-1 and rapid progression
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The Lancet June 4 2005, Number 9475, Volume 365
Martin Markowitz a and Daniel Boden a
Authors' reply
Richard Jefferys is partly correct. Descriptions of individuals with rapidly progressive disease, those infected with multidrug-resistant HIV-1, or reports of infection with viruses that use both CCR5 and CXCR4 have been well documented. Indeed, some reports have linked X4 use with rapid progression. However, Jefferys misses the critical public-health aspect of this case report. The patient engaged in a very large number of high-risk sexual contacts between the last negative serology in May, 2003, and the first positive serology in December, 2004, and these occurred in the context of methamphetamine use. In 10 years of monitoring the prevalence of the transmission of drug-resistant HIV-1 in New York City, this virus is perhaps the most resistant we have seen. That hundreds of gay men, and perhaps more, were potentially exposed to this virus was alone a cause for concern. This patient has required initial treatment with a six-drug combination regimen that may not provide both long-term suppression of viral replication and immune reconstitution.
We believe that by describing this case we have emphasised the need for better understanding of the risks of unprotected sex and recreational drug use. Discussions surrounding safe sex, methamphetamine use, screening for primary HIV-1 infection, and tracking the transmission of drug-resistant HIV-1 have been reinvigorated here in New York City and elsewhere. We believe that the report underscores the need for combined efforts of the scientific community, the medical community, those entrusted with safeguarding public health, and communities affected by HIV-1 to prevent transmission and improve outcomes.
We wholeheartedly agree with Geoffrey Gottlieb and David Nickle. Indeed we cannot rule out the possibility of dual infection or superinfection in this case, but we are exploring these possibilities. That there were discrepancies between consensus genotypes and the phenotype is explained in the paper, and is better accounted for by fast forward evolution in the absence of drug and fitness issues as opposed to superinfection and recombination.
The homogeneity of the polymerase gene in areas conferring resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors, and the heterogeneity in the areas conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs) are consistent with the abilities of the protease inhibitor mutations to be well compensated,1 the NNRTI mutations to offer little in the way of fitness compromise,2 and the complex assortment of many NRTI mutations to be poorly tolerated by reverse transcriptase.
We also agree that the ability to detect envelopes with varying tropism could be consistent with dual infection or superinfection. All analyses were done on the initial sample we obtained on this patient. We sequenced a 300 base-pair segment of env, including the V3 loop. Therefore variable tropism and limited variability in the V3 region are not contradictory. Indeed, we did see some variability in the V3 loop region that accounts for variable tropism of the different clones identified. That said, given the data, we could not account for the source of this variability, be it dual infection, superinfection, recombination, or HIV-1 variation over time as a result of in-vivo selective pressure.
We declare that we have no conflict of interest.
References
1. Brenner BG, Routy JP, Petrella M, et al. Persistence and fitness of multidrug-resistant human immunodeficiency virus type 1 acquired in primary infection. J Virol 2002; 76: 1753-61. MEDLINE | CrossRef
2. Dykes C, Fox K, Lloyd A, Chiulli M, Morse E, Demeter LM. Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants. Virology 2001; 285: 193-203. MEDLINE | CrossRef
Multidrug-resistant, dual-tropic HIV-1 and rapid progression
Martin Markowitz and colleagues (Mar 26, p 1031)1 take great pains to emphasise the putatively unique features of their described case, including the large proportion of X4 or R5X4 viruses present. However, in a review, Moore and colleagues2 write: "Rare individuals in whom X4 or R5X4 viruses predominate early after infection can lose their immune systems with stunning rapidity." Three studies, dating back to 1992, are cited in support of this statement. Also, on the basis of the extrapolations of previous cohort data contained in the Discussion section of Markowitz and colleagues' article, combined with current estimates of the number of HIV-1 infections occurring in the USA, 28 cases of progression in less than 6 months (and 180 cases of progression in less than 12 months) can be expected to occur annually.
Another justification made by Markowitz and colleagues for giving special attention to this case is that multidrug resistance has occurred in tandem with rapid progression. Multidrug antiretroviral therapy has been in use for close to a decade and several studies have shown that resistance mutations can be transmitted (albeit seemingly with less efficiency than wild-type virus).3 It was therefore inevitable that an individual with a predominance of R5X4 virus early in infection, rapid progression, and multidrug resistance would be seen at some point. It would, in fact, be strange if this did not occur.
Examples of cases of infection with X4 HIV-1 that subsequently reverts to predominantly R5 use have been published,4 as have other examples of infection with X4 HIV-1 that persists and is associated with rapid disease progression.5 The reasons for these divergent outcomes are unknown, but are thought to involve host factors, not differences in the viruses involved.3 On the basis of the data presented by Markowitz and colleagues, there is absolutely no reason to think that this case is any different. To state, as they do, that "the public health ramifications of this case are great" involves an imaginative leap unsupported by any science. In the absence of more than a single anecdote, there is no evidence that this virus will maintain the same proportions of R5 and R5X4 phenotypes in a new host (and, by extension, that it will be associated with rapid progression in a new host). None of the transmitted X4 or R5X4 viruses that have been documented over the past 20 years have done so, and Markowitz and colleagues offer no evidence that this virus is any different.
I declare that I have no conflict of interest.
References
1. Markowitz M, Mohri H, Mehandru S, et al. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report. Lancet 2005; 365: 1031-38. Abstract | Full Text | PDF (286 KB) | CrossRef
2. Moore JP, Kitchen SG, Pugach P, et al. The CCR5 and CXCR4 coreceptors-central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses 2003; 20: 111-26. MEDLINE
3. Leigh Brown AJ, Frost SD, Mathews WC, et al. Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population. J Infect Dis 2003; 187: 683-86. MEDLINE | CrossRef
4. Pratt RD, Shapiro JF, McKinney N, et al. Virologic characterization of a primary human immunodeficiency type 1 infection in a health care worker following needle stick injury. J Infect Dis 1995; 172: 851-54. MEDLINE
5. Kuritzkes DR, Bell S, Bakhtiari M. Rapid CD4+ cell decline after sexual transmission of a zidovudine-resistant syncytium-inducing isolate of HIV-1. AIDS 1994; 8: 1017-19. MEDLINE
The Lancet 2005; 365:1923-1924
Multidrug-resistant, dual-tropic HIV-1 and rapid progression
Geoffrey S Gottlieb email address a and David C Nickle a
The report by Martin Markowitz and colleagues1 of a case of HIV-1 infection with a multidrug-resistant virus and rapid progression to AIDS highlights some of the conundrums of determining whether viral factors, host factors, or both are at play in patients with very rapid progression to AIDS. We have reported an association between infection with two strains of HIV-1 (so-called dual infection) and rapid disease progression.2 On reading the current report, we wonder whether the "New York Case" might be a case of dual HIV-1 infection?
Although Markowitz and colleagues do not explicitly state whether they screened for dual infection, several areas of their investigation point to the possibility that their patient did have such an infection. First, the patient had multiple sexual partners in a short period of time. Second, there was a striking increase in HIV-1 plasma viral load between December, 2004, and February, 2005—an observation that has been seen in several cases of HIV-1 superinfection. Third, there seems to be some discrepancy between the results of drug resistance genotyping and phenotyping, possibly suggesting two populations of viruses. Fourth, two populations of viruses were noted in the coreceptor assays (an R5-tropic and a dual X4/R5-tropic isolate). Lastly, the phylogenetic tree of a single sequence from the pol gene from this patient shows an unusually divergent isolate, perhaps suggesting recombination from two independent strains.
Arguing against dual infection in this patient, Markowitz and colleagues report that the sequence diversity of p17 and the V3 loop of env was low (0-4% and 1-7%, respectively). However, at what time these samples were taken is unclear, as is whether this low diversity could represent emergence of a recombinant form or outgrowth of one strain (both phenomena have been seen in other dually infected patients).
Although these points raise our suspicion that the patient in this case may have been dually infected, only a formal analysis of the patient's viral strain (or strains) over time will rule in or out this possible explanation for his rapid disease progression. Irrespective of whether our suspicions are correct or not, they highlight the need to better understand the factors, viral and host, that lead to rapid HIV disease progression.
We declare that we have no conflict of interest.
References
1. Markowitz M, Mohri H, Mehandru S, et al. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report. Lancet 2005; 365: 1031-38. Abstract | Full Text | PDF (286 KB) | CrossRef
2. Gottlieb GS, Nickle DC, Jensen MA, et al. Dual HIV-1 infection associated with rapid disease progression. Lancet 2004; 363: 619-22. Abstract | Full Text | PDF (77 KB)
Multidrug-resistant, dual-tropic HIV-1 and rapid progression
Douglas F Nixon a, Steven G Deeks b, Barbara L Shacklett c and Annika C Karlsson a
In their report of a patient recently infected with a multidrug-resistant HIV-1, Martin Markowitz and colleagues1 state that "treatment options for our patient are limited". Although new antiretroviral drugs are being developed for such patients, it is not clear when we will have the capacity to construct fully suppressive antiretroviral drug regimens.2 To complement these regimens, new immune-based approaches such as cytokine augmentation or immunotherapeutic vaccination may be required.
Several investigators have identified regions of HIV-1 protease and reverse transcriptase that are susceptible to mutation in response to antiretroviral therapy, but are also targets for putative T-cell-mediated recognition.3-5 We and others have suggested that vaccination with drug-resistant sequences, or wild-type sequences, to specifically boost cytotoxic lymphocytes could be used to augment or alter patterns of drug resistance by mobilising immune responses.3-5 We have described one epitope in protease where strong immune pressure can apparently prevent or delay the development of drug resistance mutations.4
In the patient described by Markowitz and colleagues, the HLA class I alleles included HLA-B*350101 and HLA-B*440301. Although this patient probably does not make a robust cytotoxic T-lymphocyte (CTL) response, given the relative lack of viral containment, epitope-specific vaccination might stimulate antiviral T-cell activity. For example, there is a well-described HLA-B*44-restricted epitope in reverse transcriptase at positions 203-212.5 Theoretically, specific vaccination with strong adjuvants and a CTL-inducing peptide to the drug-resistant and wild-type sequences might elicit T cells that would recognise and control virus with the L210W mutation.
Antiretroviral therapy is effective in those that can tolerate or afford it, but the work of Markowitz and colleagues argues for new therapeutic approaches, including epitope-specific vaccinations that either prohibit the development of specific resistance-associated mutations or mobilise a response against the mutant virus.
We declare that we have no conflict of interest.
References
1. Markowitz M, Mohri H, Mehandru S, et al. Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report. Lancet 2005; 365: 1031-38. Abstract | Full Text | PDF (286 KB) | CrossRef
2. Deeks SG. Treatment of antiretroviral-drug-resistant HIV-1 infection. Lancet 2003; 362: 2002-11. Abstract | Full Text | PDF (131 KB) | CrossRef
3. Samri A, Haas G, Duntze J, et al. Immunogenicity of mutations induced by nucleoside reverse transcriptase inhibitors for human immunodeficiency virus type 1-specific cytotoxic T cells. J Virol 2000; 74: 9306-12. MEDLINE | CrossRef
4. Karlsson AC, Deeks SG, Barbour JD, et al. Dual pressure from antiretroviral therapy and cell-mediated immune response on the human immunodeficiency virus type 1 protease gene. J Virol 2003; 77: 6743-52. MEDLINE | CrossRef
5. Mason RD, Bowmer MI, Howley CM, Gallant M, Myers JC, Grant MD. Antiretroviral drug resistance mutations sustain or enhance CTL recognition of common HIV-1 Pol epitopes. J Immunol 2004; 172: 7212-19. MEDLINE
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