Were host factors or superinfection the key to case of rapid HIV progression?

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Doctors from the Multicenter AIDS Cohort (MACs) study have reported a retrospective case of HIV superinfection. The case report is published in the August 15th edition of Clinical Infectious Diseases. The investigators note that their patient became superinfected with dual-tropic HIV between eight and 15 months after his initial HIV seroconversion. This lead to a rapid increase in the patient’s viral load, although there was no significant impact on the individual’s already falling CD4 cell count.

The investigators believe that the patient’s immunological and genetic characteristics may have been important factors in his superinfection. Like all but one of the cases of superinfection reported so far, this patient’s superinfection occurred soon after his initial infection with HIV.

The frequency of HIV superinfection (or reinfection) and its consequences are largely unknown. There have been several case reports of superinfection, but such reports have been rare, and careful laboratory tests are needed to verify if superinfection has indeed occurred.

Glossary

superinfection

When somebody already infected with HIV is exposed to a different strain of HIV and becomes infected with it in addition to their existing virus.

 

strain

A variant characterised by a specific genotype.

 

disease progression

The worsening of a disease.

peripheral blood mononuclear cells (PBMCs)

Any blood cell having a round nucleus (e.g., a lymphocyte, a monocyte or a macrophage). These blood cells are a critical component in the immune system. 

tropic

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

Many of the case reports of superinfection have involved the substitution of wild-type, drug-sensitive HIV, with drug-resistant strains of the virus. Recombination of HIV subtypes has also been described as a consequence of superinfection. Coinciding with superinfection, many of the cases so far reported experienced a significant rise in their viral load and loss of CD4 cells. It is unclear if superinfection leads to more rapid HIV disease progression, and if so, the reasons for this.

Most individuals become infected with strains of HIV that use the CCR5 co-receptor. However, initial infection with HIV that utilises the CXCR4 co-receptor, or with so-called dual tropic HIV that uses both R5/X4, has been reported and is associated with faster HIV disease progression. Interest in initial infection with dual-tropic HIV and its consequences for disease progression was excited by the case of the so-called New York patient.

Investigators from the MACS cohort retrospectively identified a 39 year-old Hispanic man who was initially infected with HIV in 1992. The patient’s CD4 cell count was over 800 cells/mm3 at the time of his diagnosis, but had fallen to under 200 cells/mm3 a little over two and a quarter years later, and the patient developed PCP pneumonia just over three years after his HIV diagnosis. He died six years after his diagnosis with HIV.

Phylogenetic analysis indicated that the patient became superinfected with a second strain of HIV between eight and 15 months after his initial HIV infection. In the six month prior to his superinfection, the man reported multiple instances of unprotected anal sex with over 20 sexual partners. No acute viral syndrome was reported at the time of superinfection.

The two CD4 cell counts taken before superinfection were 558 cells/mm3 and 360 cells/mm3. The investigators calculated that the patient’s CD4 cell count was already declining sharply before superinfection and that reinfection with a second strain of HIV did not accelerate this loss.

Phylogenetic analysis showed that both the initial and superinfection strains were HIV subtype-B. There was no evidence of the superinfection strain in either plasma or peripheral blood mononuclear cells (PBMC) before 15 months after initial infection.

The superinfecting strain rapidly overtook the first strain of HIV in plasma eight to 15 months after initial infection.

Three years after the man’s HIV seroconversion, there was no trace of the strain of HIV which the patient was initially infected with.

In PBMC the superinfecting virus dominated by month 15. Between the last visit when the patient only had evidence of his initial virus and superinfection the individual’s viral load increased from 25,000 copies/ml to 87,000 copies/ml. HIV DNA concentrations in PBMC increased from 327 copies per 106 PBMCs to 1989 copies per 106 PBMCs.

Different HIV coreceptors were used by the initial and superinfecting viruses. Phenotypic and genotypic testing revealed that the patient was originally infected with HIV that used the CCR5 coreceptor, but became superinfected with dual-tropic X4/R5 virus.

No unusual genetic sequences could be detected in either the initial or superinfecting HIV strains and the superinfecting strain could not be linked to any known strain in the HIV Sequence Database.

Genetic tests suggested that the patient may have had predisposing factors that could have contributed to more rapid HIV disease progression, particularly carriage of a human haplogroup E haplotype and partial homozygosity at class I loci. The investigators comment, “this superinfected subject displayed some genetic susceptibility to rapid disease progression.” Indeed, the investigators believe that host factors, rather than superinfection may have been responsible for their patient’s rapid HIV disease progression. They highlight four factors that suggest that this was the case:

 

  • The patient’s rapid fall in CD4 cell count preceded superinfection.
  • X4 virus is uncommon in infecting strains.
  • No evidence was found in epidemiological databases to suggest that the superinfecting strain in this individual has been found in other patients. However, the retrospective nature of the analysis, and the death of the patient, made contact tracing impossible.
  • The patient carried genetic markers related to poor immunological response and poor prognosis.

 

The investigators speculate that the patient may have been susceptible to superinfection because of his rapidly weakening immune system.

They conclude, “as additional cases of superinfection emerge, the perception that host immunity induced by primary HIV-1 infection is generally protective against acquisition of a second virus…may need to be re-evaluated.”

References

Gottlieb GC et al. HIV type 1 superinfection with a dual-tropic virus and rapid progression to AIDS: a case report. Clin Infect Dis 45: 501 – 509, 2007.