IAS: The New York Patient - source found but mysteries remain

The source of infection for the New York gay man whose multi-drug-resistant and apparently virulent stain of HIV caused a public health alert earlier this year has apparently been found.

Dr Gary Blick, an HIV physician from Norwalk in Connecticut, told the Third International AIDS Society Conference in Rio de Janeiro that the virus came from one of his patients, a 52-year-old gay man who had been diagnosed in 1993.

But the identification of the ‘Source Patient’ who infected the New York Patient raises more questions than answers, some of them troubling. Specifically:

• New York (‘Index’) Patient may have been infected by someone with a plasma viral load as low as 1,500 copies/ml.
• Though 99.5% similar to that in the Index Patient, the virus did not cause ‘rapid progression’ in the Source Patient.
• The Index Patient’s virus was dual-tropic - it could bind to both CCR5 and CXCR4 co-receptors - but the Source Patient’s was purely a CCR5 virus.
• The Index Patient’s virus was 136% as virulent as wild-type virus – very unusual for a multi-drug-resistant strain. In contrast the Source Patient’s virus had a replicative capacity of only 41% of a wild-type.
• Index Patient had sex with the Source Patient’s partner too. It now appears that this patient (the ‘Source Partner’) only became multi-drug-resistant when he was superinfected with a second strain of HIV by his partner, some time in 2002.

After New York City Health Commissioner Thomas Frieden issued a press release that a patient had been diagnosed with a strain of HIV that was "difficult or impossible to treat" and which was "associated with rapid progression to AIDS", an intensive search of over 135,000 viral isolates in United States' diagnostic laboratories was made.

Frieden announced in March that a match for the New York Patient’s virus had not been found. In fact, Dr Blick told the conference, he had been alerted on February 17 by Quest Diagnostics of San Juan Capistrano in California that they had found one virus whose pol gene (which contains the reverse transcriptase and protease sequences) was 99.5% similar to the Index Patient’s, and that it came from his patient.

This patient was started on AZT (zidovudine, Retrovir) monotherapy in 1995 with a CD4 cell count of 95 cells/mm³ and then took a succession of suboptimal regimens featuring all three then-available classes of antiretroviral. However, unlike the Index Patient, he did not progress to AIDS rapidly. Like the Index Patient (and contrary to the initial press reports), he remained sensitive to the NNRTI drugs efavirenz (Sustiva) and delavirdine.

In February 2004 he was put on a ‘mega-HAART’ combination of T-20, efavirenz, boosted saquinavir and three NRTIs. This resulted in his viral load falling below 400 copies/ml and his CD4 cells rising to 310 cells/mm³. However, he stopped taking his T-20 for four days in October 2004, and was immediately given a viral load and resistance test, which Quest genotyped on 10^th October.

This revealed his viral load was 1,450 copies/ml and that he had a pattern of 20 resistance mutations later found to be almost identical to that in the New York Patient (who had one extra NRTI mutation). The Source Patient later reported that he and his partner had visited the West Side sex club in New York soon after this, on the weekend on 22-24 October. They had both had insertive anal intercourse under the influence of methamphetamine with the Index Patient – who identified the Source Patient by a physical description.

Blick continued that he was later alerted to the presence of a second viral isolate which was 98.5% similar to the index patient’s. This sample had been collected in August 2002 and belonged to the Source Partner, who was diagnosed in 1994.

When previous blood samples from this third patient were tested, it turned out he had non-resistant wild-type virus up until September 2001, but by September 2004 was resistant to all HIV drugs except T-20 (including efavirenz) though with a stable viral load and no decline in CD4 cells.

The couple had practiced unprotected anal intercourse both within their relationship and outside it, and had a history of STIs including anal warts, syphilis and community-acquired MRSA.

By sequencing the entire pol gene of both partners, Blick was able to show that the virus in the Source Partner was now a recombinant form of his original virus and his partner’s. This is despite that fact that he had had HIV for eight years already and superinfection was thought to be rare in people with more than three years’ experience of HIV infection, due to the buildup of innate immune responses.

Blick told the conference: “Neither of the presumed contact partners was considered to have experienced accelerated disease progression”. He added that the Source Patient’s virus was only CCR5-tropic, and that it was less, rather than more, virulent than wild type.

However, answering a question from the audience, Dr Blick said that RC assays were so imprecise that the difference might be more apparent than real. The minimum RC of the Index Patient’s virus could be as low as 86% of wild-type, and the maximum RC of the Source Patient’s could be 65%, allowing for a near-overlap, especially as RC had been tested at different times.

Many questions remain unanswered by this puzzling case. In particular:

• Did the Source Patient continue to stay off T-20? And if so, what was his viral load by October 22?
• Did either the Source or Index Patients have concurrent sexually transmitted infections that could have facilitated transmission?
• How did the Index Patient’s virus become dual-tropic?
• And, above all, what was the cause of his rapid immunological decline and was it tied to his crystal meth use?

The identification of the source virus has clearly not concluded this case.