Two US research groups today report that the scale of HIV infection of lymph nodes in early and asymptomatic HIV infection is far more limited than hitherto believed, raising the possibility, according to one group, that removal of the viral reservoirs provided by selected lymph nodes in asymptomatic individuals may allow longer treatment interruptions.
Both groups used a technique called positron emission tomography (PET) scanning to identify lympoid tissue that was packed full of activated lymphocytes. These white blood cells are drawn to lymph nodes that are focal points of HIV infection. PET scanning is able to identify activated lympocytes by tracking levels of radiolabelled glucose, since activated lymphocytes increase their glucose uptake 20-fold.
Lymph nodes are the main reservoir of HIV infection, and PET scanning has revealed that people with early or non-progressive HIV infection (either recent seroconversion or a CD4 count above 400 cells/mm3) have little sign of HIV activity in lymph nodes below the chest. Outside the lymph nodes, PET scanning could not detect substantive levels of lymphocyte activation, indicating that the vast majority of virus activity in the body is concentrated in the lymph nodes and lymphoid tissue such as the spleen.
A group from Johns Hopkins University School of Medicine reported on 12 recent seroconverters and 11 HIV-positive untreated individuals with CD4 cell counts above 400 cells/mm3 and viral loads ranging from undetectable to 52,000 copies/ml. All the latter group had stable viremia (fluctuating less than 0.5 log over three measures). Whilst recent seroconverters had wide-ranging lymph node involvement, the asymptomatic group showed little involvement of deeper lymph nodes in the torso. Instead, lymph nodes in the neck and upper torse tended to be much more strongly activated than lower torso lymph nodes. The ratio of activation between upper and lower body, as measured by PET signal intensity, varied from 3:1 to 18:1.
One individual was scanned prior to therapy, and again during a one month treatment interruption that took place after six months of therapy and one month of viral suppression below 50 copies/ml. Viral load peaked at around 10,000 copies/ml after one month off treatment, and the pattern of lymph node involvement during the treatment interruption matched the one seen in recent seroconverters. Of particular note, no lymph nodes unactivated at the time of the first PET scan became activated during the treatment interruption.
In a second study carried out by the University of Wisconsin, Dr David Pauza (now at the Institute of Human Virology, University of Maryland) evaluated lymph node activation by PET scan in 15 HIV-positive patients at various stages of disease progression. He found a clear anatomical pattern: as HIV disease progressed, the number of lymph nodes activated began to increase, and the focus of activation moved from the head and neck down the torso, until in late stage disease the lymphoid tissue in the gut became heavily activated. In one patient close to death with no CD4 cells, the only sites of activation were the rings of lymphoid tissue at the ileocaecal junction, the point at which the large intestine meets the small intestine. The authors of this study speculate that these rings of lymphoid tissue are the last reservoir of HIV in the body.
His findings challenge accepted wisdom about the extent of viral reservoirs in HIV-infected people. Previous research has suggested that the lymph nodes in the gut are the biggest reservoir of HIV in most people with HIV.
The authors of both studies suggest that surgical removal of lymph nodes may be an option.
Dr David Schwartz suggests that removal of lymph nodes should be investigated. “Although many systemic sites from which latent virus could reactivate would be left, reactivation might not occur for months or years after removal of the active nodes, thereby allowing extended interruptions of treatment.”
Dr Schwartz told aidsmap: “Any of the nodes we visualised would be accessible with minor surgery done under limited anesthesia, as for lymph node excisional biopsies for cancer), but only highly experienced surgeons should be involved in these kinds of operations, as these nodes lie near to major blood vessels and nerve tracts in the axilla and neck. The inguinal nodes are the easiest to work with when they are involved, but that will generally only be the case when there are upper nodes involved as well. A key point would be the use of intraoperative PET probes to identify the "hottest" most active nodes in the region. Nonsurgical targeted radiation might be another way to go.”
Dr Pauza suggests that surgery might be used to identify remaining sites of viral activity after long-term suppressive therapy, an approach he says is already common in cancer therapy.
The findings also raise interesting questions about the targeting of HIV therapy. If the main sites of replication are so restricted, doesn’t it make sense to look at ways of delivering drugs much more intensively to lymphoid tissue in preference to other parts of the body that don’t need to be saturated?
In particular, the findings raise questions about the targeting of chemokine inhibitors. Dr Schwartz’s group suggest that selection of CCR5-tropic virus during earlier HIV infection reflects not only a selective advantage in the presence of relatively intact immunity, but an environmental advantage in the setting of peripheral lymph nodes. Would targeting of the lymph nodes result in much greater reduction in viral burden in less advanced HIV disease?
More specific targeting of the burden of activated cells might be coupled with strategies to activate latently infected cells, such as the combination of immunotoxin and interleukin-7 stimulation described this week in another article published in the Journal of Clinical Investigation (click here to read a news report on that study).
“With respect to targeting immunotoxins more efficiently, I am sure that if immunotoxins can be anatomically targeted, then PET scanning for active nodes would be extremely valuable in many cases. The ability to anatomically target immunotoxin delivery is probably the bigger obstacle at this time,” said Dr David Schwartz.
The ultimate aim of all these approaches would be to reduce the viral burden so that any treatment interruption would result in a smaller viral rebound. The next experiments in this direction will need to look at whether there is a correspondence between the degree of lymph node activation, viral burden in the lymph nodes on treatment and the degree of viral rebound after treatment is interrupted. If a correlation is shown, the next step would be to test whether targeting the lymph nodes, either by surgery or treatment, would reduce the extent of rebound when treatment was stopped.
Iyengar S et al. Anatomical loci of HIV-associated immune activation and association with viremia. The Lancet 362: 945-950, 2003.
Scharko AM et al. Whole body positron emission tomography in patients with HIV-1 infection. The Lancet 362: 959-961, 2003.