The Boston Globe this morning reports:-

HIV virus returns after cure hope rose

2 Boston patients had transplants of marrow, halted powerful drugs

 

This story is being picked up by multiple news outlets now, including the NY Times and NPR. The findings were reported by Dr Timothy Henrich of the Brigham and Women’s Hospital in Boston, at the Sixth International HIV Persistence Workshop, December 3-6 2013, Miami, Florida. 

While the new data are obviously very disappointing, they are also very interesting. One important ramification of viral break-throughs in the Boston patients, is that it suggests that the CCR5 delta-32 homozygous bone marrow transplant (BMT) the Berlin patient received may have been critically important in the apparent success of his “cure”. The Berlin patient was CCR5 delta32 heterozygous (copies of the mutant gene at only one of the two parental gene alleles) before his BMT. This mutant genotype is known to have some protective effect against disease progression once infected HIV, though not against becoming infected with HIV. Individuals who are CCR5 delta-32 homozygous (copies of the mutant gene at both parental gene alleles), are thought to have a considerable degree of protection against becoming infected HIV.

There are at least two important considerations to make regarding the impact of CCR5 delta-32 in the “cured” Berlin patient.

The first is that his natural CCR5 delta-32 heterozygous genotype may mean that he did not harbour the same cellular reservoirs of HIV as other HIV-infected individuals who do not have the CCR5 delta-32 mutation.

The second important consideration is that the transplant bone marrow tissue the Berlin patient received was CCR5 delta-32 homozygous. In theory the cells that are homozygous for the CCR5 delta-32 mutation can not be infected by the majority of circulating HIV strains in the body.

With this in mind, the news of the Boston patients’ viral break-throughs suggest that the whole bone marrow transplant strategy for curing HIV can only succeed if the transplant is CCR5 delta-32 homozygous.

Again, a note of caution needs to be added because there is the confounding factor that the Berlin patient was CCR5 delta-32 heterozygous before his transplant. This may mean that certain cell populations in his body, that could potentially harbour long-lived HIV reservoirs, were not permissive to infection with HIV before his antiretroviral treatment was started. Scientists agree that the major reservoir of HIV in people on long-term antiretroviral therapy, exists in resting memory CD4 T cells. Reservoirs may  also exist in other parts of the body, such as in microglial cells in the brain or in the bone marrow or testes, though this is not known for certain. But if the establishment of such alternative cell populations as HIV reservoirs is dependent on their expression of CCR5, then a CCR5 delta-32 heterozygous phenotype may prevent that from happening. The case of microglia are especially interesting because they are unlikely to be affected by the myloablative therapy given before a bone marrow transplant. This means that any reservoir in the microglia are unlikely to have been eradicated by the cytotoxic chemotherapy given before bone marrow transplantation in the Berlin patient. Whereas potential reservoirs in the bone marrow would be affected by this therapy. Therefore the “cure” of the Berlin patient would seem to suggest that the microglia in the brain are not a major reservoir for HIV, otherwise this approach to a cure would not have worked. But this is only the case if we know that in the Berlin patient, the microglia reservoir ever actually existed in the first place, and was not somehow prevented by his CCR5 delta-32 heterozygous genotype.

This therefore complicates the story of the Berlin patient. Was the success of his apparent “cure” because of his prior CCR5 delta-32 heterozygous genotype? Interestingly the Boston patients were also apparently CCR5 delta-32 heterozygous as well, so the defective microglial reservoir theory looks less likely to be the case. Alternatively was the success of he Berlin patient’s “cure” because of the CCR5 delta-32 homozygous genotype of the transplant he received. Or could it be that both a natural CCR5 delta-32 heterozygous genotype and a CCR5 delta-32 homozygous transplant are required together?

Either way, viral breakthrough in the Boston patients suggests at least that the CCR5 delta-32 homozygous genotype of the transplant was a critical feature for the success of this strategy in the Berlin patient.

Some important questions for the Boston team to address must surely include sequencing of rebounding virus in the Boston patients. Is there evidence that this virus is derived from a single clone or restricted cellular source? Is it representative of viral sequences found in the Boston patient’s resting memory CD4 T cells. Is there evidence for chemokine receptor usage in the envelope sequences that could point to potential sources? Could this virus in fact be derived from microglia in the brain that were unaffected by chemotherapy?

These are important considerations to make in evaluating the ramifications of “cure” failure in the Boston patients and “cure” success in the Berlin patient and what this means regarding the identity of persisting HIV reservoirs and their potential for clearance.