HIV-Specific Helper Cells:"Non-Progressors" Spur Progress

HIV-Specific Helper Cells:
"Non-Progressors" Spur Progress

by Jeremy Cherfas

WHAT'S HOT IN BIOLOGY...

Rank	Paper	Citations This Period Sep- Oct 99	Rank Last Period Jul- Aug 99
1	S. F. Altschul, et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs," Nucleic Acids Res., 25(17):3389-3402, 1 September 1997. [NIH, Bethesda, MD; Pennsylvania St. U., University Park] *XU793	190	1
2	F.R. Blattner, et al., "*The complete genome sequence of Escherichia coli* K-12,"** Science, 277(5331):1453-74, 5 September 1997. [U. Wisconsin, Madison; U. Michigan Sch. Med., Ann Arbor; FMC Bioproducts, Rockland, ME; U. Natl. Autonoma Mexico, Moreles] *XV429	73	3
3	F. Kunst, et al., "*The complete genome sequence of the Gram-positive bacterium Bacillus subtilis,"* Nature, 390(6657):249-56, 20 November 1997. [46 institutions worldwide] *YG667	64	7
4	M. Enari, et al., "A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD," Nature, 391(6662):43-50, 1 January 1998. [Osaka U. Med. Sch., Japan; Kirin Brewery Co., Kanagawa, Japan; Osaka Biosci. Inst., Japan] *YP888	58	9
5	P. Li, et al., "Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade, " Cell, 91(4):479-89, 14 November 1997. [Howard Hughes Med. Inst., U. Texas Southwest. Med. Ctr., Dallas; Thomas Jefferson U., Philadelphia, PA] YG492	55	4
6	H.-P. Klenk, et al., "*The complete genome sequence of the hyperthermophilic, sulphate-reducing archaeon Archaeoglobus fulgidus,"* Nature, 390(6658):364, 27 November 1997. [Inst. Genomic Res., Rockville, MD; Argonne Natl. Lab., IL; U. Illinois, Champaign-Urbana] *YH549	51	†
7	D.A. Doyle, et al., "Structure of the potassium channel: Molecular basis of K⁺ conduction and selectivity," Science, 280(5360):69-77, 3 April 1998. [Rockefeller U., New York, NY; Howard Hughes Med. Inst., Rockefeller U., NY] *ZF314	48	2
8	D.R. Smith, et al., "Complete genome sequence of Methanobacterium thermoautotrophicum d-H: Functional analysis and comparative genomics," J. Bacteriology, 179(22):7135-55, November 1997. [Genome Therapeutics Corp., Waltham, MA; Howard Hughes Med. Inst., Harvard Med. Sch., Boston. MA; F. Hutchinson Cancer Res. Ctr., Seattle, WA; Ohio State U., Columbus] *YG075	45	†
9	S.R. Datta, et al., "Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery," Cell, 91(2):231-41, 17 October 1997. [Harvard Med. Sch., Boston, MA: Emory U., Atlanta, GA] YC350*	41	10
10	S.T. Cole, et al., "*Deciphering the biology of Mycobacterium tuberculosis* from the complete genome sequence,"** Nature, 393(6685):537, 11 June 1998. [Sanger Ctr., Hinxton, England; Inst. Pasteur, Paris, France; NIAID, NIH, Hamilton, MT; Tech. U. Denmark, Lyngby] *ZT988	40	6

SOURCE: ISI's Hot Papers Database. Read the full legend.

wenty years or so ago, human immunodeficiency virus seemed like a very odd organism. Just outside the Top Ten, at #12, is a paper that casts HIV as just another virus (E.S. Rosenberg, et al., "Vigorous HIV-1 specific CD4⁺ T cell responses associated with control of viremia," Science, 278(5342):1447-50, 21 November 1997; cited 34 times this period). In particular, Bruce Walker and his team at the Partners AIDS Research Center of Massachusetts General Hospital show that the immune system is capable of responding to HIV, and that this response is a very important component of the body's ability to control viremia, the level of virus circulating the blood. "HIV follows the rules that other viruses follow—that's what's so important," Walker tells Science Watch. "It's not something that marches to its own drum. It's doing things in a predictable way."

Walker has spent his research career looking at the immune system correlates of HIV. His is the first group to show a clear association between a virus-specific immune response and the ability to control the virus. The paper demonstrates a clear association between strong responses by cytotoxic cells and by helper cells. "The evolving notion is that people control viremia because they have CD4⁺ cells that provide help to the CD8⁺ cells," Walker explains. "It is the CTL [killer] cells that mediate the control, but they need virus-specific helper cells." The vast majority of HIV-infected people have undetectably low levels of CD4⁺ helper cells. But these cells can be induced.

This fascinating discovery came about because of earlier work showing that cytotoxic T cells were an important part of the response to HIV. That surprised people at the time because the received wisdom was that HIV dismantled the immune system. It was as a result of that work that a very unusual patient landed on Walker's doorstep. He was a hemophiliac who could document the start of his infection more than 18 years before. "As clinicians we were all seeing patients come in, get worse, and die," Walker said. The hemophiliac patient simply had no problem. Walker's response was simple: "This guy is doing something other people aren't." The voluntary arrival of subject 161-J, whom Walker describes as a "critical" individual for the understanding of HIV, prompted an in-depth immunological study.

Walker is quick to point out that 161-J's survival has "absolutely nothing to do with the mode of transmission." In fact, it seems that one or two percent of the population has the ability to keep the virus under control—to become, in the jargon, non-progressors. And Walker's results point the way to helping others achieve similar status.

What seems to be happening is that when people first get infected, the CD4⁺ helper cells are activated. Unfortunately, HIV preferentially attacks those activated CD4⁺ cells, so they are not in a position to offer much in the way of help to the killer CD8⁺ cells. But reducing the viral load with drugs, at the same time as inducing viral-specific CD4⁺ cells with a vaccine, could allow chronically-infected patients to control the disease. In effect you would give intermittent therapy, boosting the immune response by re-exposing the patients to their own virus. Walker describes the approach as "structured treatment interruptions," and points out that the paper suggests such a regime "deserves to be tested."

And it has been. A couple of ongoing studies have taken up the challenge. Walker's group has a trial in which patients have been given either a vaccine against HIV or a control vaccine. "The next step will be to take them off therapy and see whether they can control the virus," Walker tells Science Watch.

The reality is that most viral infections are not eliminated, but are just controlled by the immune system. Diseases such as chicken pox or mono remain in the body, possibly to flare up and then be brought back under control. "We now have evidence that HIV can be held in check," Walker says. "And we're getting closer to having a target to aim at for inducing immune responses in people who are not controlling the virus."

Science writer Dr. Jeremy Cherfas
works with the Biotechnology and Biological Sciences
Research Council of the U.K., Swindon.

Science Watch^®, January/February 2000, Vol. 11, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2000/sw_jan-feb2000_page8.htm