The ‘New York case’: details revealed at Boston conference

Christopher Gadd, Theo Smart
Published: 25 February 2005

In response to recent media reports about a New York man apparently infected with an ‘aggressive’ strain of HIV that is ‘impossible to treat’, attendees at the Twelfth Annual Retrovirus Conference heard what is known – and what is not known – about the case, at an additional session on Thursday evening.

The case of a gay man in his 40’s who had recently become infected with HIV and experienced rapid disease progression received widespread media attention at the beginning of February. Fuelled by the fact that the man was a user of methamphetamine and had had numerous sexual partners, the media was quick to pick up on the story and warn of the dangers of drug abuse and promiscuity.

However, as explained in a recent commentary, these reports were based on a single press release that contained little medical or scientific information.

At Thursday’s session, David Ho of the Aaron Diamond AIDS Research Center summarised the case, and the results of medical tests carried out to understand the nature of his rapid disease progression. He emphasised that the case is unusual, as it represents a convergence of multi-drug resistant HIV and rapid disease progression in a single patient.

However, he also emphasised that this isolated case report does not indicate that the HIV strain found in this patient is aggressive, since disease progression is determined by the complex interaction between the virus and the host’s genetic make-up.

Similarly, he pointed out that there is no evidence to help identify whether this is an isolated case, or part of a larger cluster of similar cases. As described by Harold Jaffe of the University of Oxford, this may be determined by the ongoing investigations into this patient’s sexual contacts and the epidemiology of this drug-resistant strain of HIV.

Rapid progression

Dr Ho confirmed that the man had had his last negative HIV test in May 2003. After developing fever, sore throat, weakness and fatigue, he tested positive for HIV in December 2004.

On HIV diagnosis, his CD4 cell count was 80 cells/mm3 and viral load was 280,000 copies/ml. By mid-January 2005, his CD4 cell count had fallen to 28 cells/mm3, and he had lost 4kg in weight by the start of February. It appears that the patient’s AIDS diagnosis was made on the basis of his low CD4 cell count alone. It should be noted that severe CD4 loss, followed by immune restoration, has been reported in primary HIV infection in the past.

Although the exact date of the patient’s HIV infection is not known, his progression from HIV negative in May 2003 to ‘AIDS’ in a maximum of 20 months does indicate an unusually rapid disease progression. As explained in a presentation by Stephen Gange of Johns Hopkins Bloomberg School of Public Health, similar rapid progressions have been observed before, notably in the Multicenter AIDS Cohort Study (MACS), albeit with an expected frequency of less than 7 in 10,000 cases for progession within six months.

When aidsmap asked Dr Ho what evidence there was that the man is progressing to AIDS, he responded, “the patient is progressing because he has [few] CD4 cells left.” Dr Ho explained that the patient was past the point of acute infection when CD4 cell counts can fall quite low. “He is already beyond acute infection and his CD4 cell count remains exceedingly low.”

He added, “there has been lots of talk of people who have seen this. [But] according to the literature, the acute infection database and the MACS database [the multicenter AIDS cohort study in which gay HIV-positive and -negative men have been followed for many years] such a case is extremely unusual. Look at facts, not people’s anecdotes.”

Treatment options

Genotypic testing revealed that the patient’s HIV contained multiple resistance mutations, including mutations at numerous codons of the reverse transcriptase gene: 41, 67, 118, 184, 210, 215 and 219.

These mutations were predicted to cause resistance to thymidine analogues, 3TC (lamivudine, Epivir) and FTC (emtricitabine, Emtriva), as well as to reduce susceptibility to abacavir (Ziagen) and tenofovir (Viread). The combination is likely to render most nucleoside analogues (NRTIs) ineffective in this patient.

Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was also predicted from the presence of mutations Y101E and Y181I, while the presence of numerous protease mutations conferred resistance to all available protease inhibitors.

However, rather than being ‘impossible’ to treat,’ phenotypic analysis of the virus revealed that it is fully susceptible to two antiretrovirals: efavirenz (Sustiva) and to the fusion inhibitor T-20 (enfuvirtide, Fuzeon). Consequently, the patient has started to take a combination of these two drugs, but no data are available on his response yet.

An ‘aggressive’ strain?

The replication capacity of the patient’s HIV was measured using the PhenoSense assay, and found to by 1.38 times greater than wild-type virus. This means that the patient’s HIV has managed to retain its ability to replicate, despite the presence of numerous resistance mutations.

In addition, analysis of the co-receptor used by HIV isolated from the patient to enter its target cells revealed that it was ‘dual-tropic’ - able to use both CCR5 and CXCR4 co-receptors. Around 60% of the virus particles were found to be ‘R5’ viruses and the remainder dual-tropic ‘R5X4’ viruses.

Consequently, the isolated HIV was able to form syncytia in two types of cell culture tested: these types of virus are usually seen late in the course of HIV infection and are associated with more rapid disease progression.

This laboratory finding was also confirmed in a sample of CD4 T-cells taken from the patient’s blood and from the gut mucosa. Levels of T-cells co-expressing the CXCR4 receptor were found to be exceptionally low in both populations of cells.

Sequence analysis of the virus’s genome revealed that this is a new strain of subtype B that has not previously been seen. It does not correspond to any viruses previously seen by the Aaron Diamond AIDS Research Center or in the Los Alamos National Laboratory Database.

However, the sequence analysis did reveal a relatively low level of diversity within the patient’s HIV sample, of less than 2%, which is consistent with recent infection and argues against the possibility that the patient became infected on more than one occasion.

The possibility that the rapid fall in CD4 cell count is simply due to primary infection with an X4-tropic virus is, however, unlikely, since the results of a detuned immunoassay were positive. This indicates that the patient is beyond the stage of acute HIV infection.

Finally, the patient was not found to possess any genes known to be associated with more rapid HIV disease progression or HLA homozygosity. However, it is not possible to discount the effect of the patient’s genetic make-up on the basis of this finding, as our understanding of how genetics influences disease progression is still in its infancy.

Taken together, this case of rapid progression is an interesting medical phenomenon that is probably representative of the tip of a wider spectrum of disease progression rates. Whether this is due to an exceptional HIV strain or an exceptional patient cannot be determined from the information available.

However, what is clear, Dr Jaffe pointed out, is that the case highlights the failure of existing HIV prevention strategies for gay men: “This case should not be used to scare people,” he said, “but it should be used to remind them of the risks of HIV.”

Reference

Markowitz M et al. A case of apparent recent infection with a multi-drug-resistant and dual-tropic HIV-1 in association with rapid progression to AIDS. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 973B, 2005.

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