An uncontrolled, single-blind clinical trial of a potential AIDSvaccine has demonstrated total efficacy in its one trial patient.

He is a 44-year-old man with hemophilia, who contracted his HIV-1infection sometime before 1983 from a contaminated bloodtransfusion. Despite testing positive for the virus, he has suffered nosymptoms of AIDS or its related diseases, and lives a normal, fulllife. His CD4 count -- a quantitative gauge of virus infection --remains at a steady healthy level today, 12 years later.

The likeliest explanation for this man's almost unique escape fromAIDS, whose victims usually die within a decade of infection, is agenetic defect in the virus that adulterated his donor blood in theearly 1980s.

A "Brief Report" in today's New England Journal of Medicine(NEJM) spells out that surmise under the title: "Absence of Intact nefSequences in a Long-Term Survivor With Non-Progressive HIV-1Infection."

That nef sequence is one of the nine genes in the AIDS virus genome.Other than that it's involved in pathogenesis, nef's function isunknown. However, when it's missing, as in the HIV-1 that infectedthe 44-year-old patient, the virus apparently fails to get in itspathogenic and ultimately fatal licks.

Virus Protected Primates -- Plus One Person

Nef is no stranger to Ronald Desrosiers, principal author of today'sNEJM paper, who chairs microbiology at the New England PrimateCenter in Southboro, Mass. He has inoculated rhesus monkeys withlive SIV-1 from which he deleted the nef gene, and obtained strikingimmunity to subsequent challenges with live, virulent strains of thevirus.

Desrosiers concluded his brief NEJM report: "The finding of onlyHIV-1 variants with nef deletions in a healthy man with long-termnon-progressive HIV-1 infection provides additional impetus forconsideration of this vaccine approach."

He gave primary impetus to the approach in a research anddevelopment partnership with Therion Biologics Corp. ofCambridge, Mass. For six or seven years, he and Therion's president,vaccinologist Dennis Panicali, have been cooperating. Early last year,Panicali told BioWorld Today, they extended their effort todeveloping an AIDS vaccine based on the nef-deleted gene.

Millions for Defense: Funding New AIDS Vaccines

"We are looking at the manufacturing and testing side," Panicali said,"as well as scale-up of material for submitting an investigational newdrug [IND] application to FDA." Therion expects to have stockpiledsufficient vaccine "within a year or two," Panicali added, "but thatdoesn't mean Phase I trials will begin just then."

Therion holds licenses to pending patents filed by HarvardUniversity, and is developing a live attenuated AIDS vaccine, basedon permanently deleting the nef gene.

The company has received $5-million from the National Institute ofAllergy and Infectious Diseases (NIAID) to pursue development ofHIV vaccines. NIAID at the same time awarded Desrosiers $6million to advance his minus-nef HIV-1 experiments.

Under development right now, Panicali said, is a newer vaccine,HIVECD4, in which nef plus three other HIV genes _ vpr, vpu andNRE _ have been deleted, for enhanced safety.

But the attenuated live-virus vaccine strategy is far from a done deal.Panicali calls it "controversial" because all candidate HIV-1 vaccinesto date are based on recombinant, subunit, antigenic, viral proteins.These have proven safe but so far ineffective.

Desrosier emphasizes that of the 11 viral vaccines now on the market,six -- including measles, mumps, polio and rabies -- are based onlive attentuated viruses.

His striking one-patient finding doesn't account for the one in 20individuals infected with HIV-1 who lead long symptom-free lives.Without dismissing the absent nef gene out of hand, other researchersexplain the five percent of "non-progressors," by invokingunaccountably robust immune defenses for one thing, or inexplicablyweakened virus strains for another.

Two other major patient studies in the same Jan. 26 NEJM exploreall three sets of theories as to these special circumstances:

In one, David Ho, who heads New York University's AaronDiamond AIDS Research Center, studied 10 seropositive patients, allwith high-risk life-styles, who remained asymptomatic, with normalCD4+ lymphocyte counts, despite 12 to 15 years of HIV-1 infection.Polymerase chain reaction assays found that all had low viral titers intheir peripheral blood. "Overall," Ho reported, "the viral burden inthe plasma and [blood] of long-term survivors was orders ofmagnitude lower than that typically found in subjects withprogressive disease."

He concluded that long-term survival depended on a combination ofall three factors _ low virus levels, strong immune responses and"some degree of attenuation of the virus."

In the second study, five universities and three other centerscompared 15 volunteer HIV-infected "non-progressors" with 18subjects suffering from progressive disease. The former had low butreplicating levels of virus in blood and lymph nodes and "virtuallyunimpaired immune function," that report stated.

Anthony Fauci, who heads NIAID, as well as its Laboratory ofImmunoregulation, which conducted the study, observed: "Thesefindings suggest that low-level, persistent HIV replication may notnecessarily be associated with disease progression if efficientlycontrolled over time."

He too suggested that further understanding of the immune systemand less virulent viral strains "may prove critical to . . . thedevelopment of new vaccines and treatments for HIV infection."

Nobelist David Baltimore, co-discoverer of reverse transcription,observed that people with true non-progressive infection "are likely to be heterogeneous, with someharboring a genetically unique virus and others enjoying an unusuallyeffective immune response to an ordinary strain of HIV."

In an editorial commenting on all three NEJM papers, Baltimore,who holds an endowed chair of molecular biology and immunologyat Massachusetts Institute of Technology, recalled that "monkeysinfected [by Desrosiers] with simian immunodeficiency virusharboring nef deletions also have non-progressive infection,suggesting that in this one rare [human] case, the cause of the non-progression may have been found."

But Baltimore qualified this optimism by observing that "manyinvestigators have sought evidence of nef deletions in the virus fromothers with non-progressive infection, but to no avail so far." Hespeculated that "other lesions will be found in other viral strains frompatients with non-progressive infections."

Baltimore added that patients with AIDS rarely show signs ofharboring more than one circulating strain of virus; i.e., they areimmune to a second infection. This had proven to be the case withDesrosier's inoculated monkeys. He reflected: "It is an irony of thisawful disease that an infected person's immune reaction can beeffective enough to prevent secondary infections, but not effectiveenough to eliminate the primary infection." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.