Re: Re: Re: Reply to Morrell: Regarding 'endogenous entities' and 'epiphenomena' 21 February 2005
Previous Rapid Response Next Rapid Response Top
Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse NY

Send response to journal:
Re: Re: Re: Re: Reply to Morrell: Regarding 'endogenous entities' and 'epiphenomena'

Regarding the Ho paper I cited (Ho et al NEJM 1989 321:pp 1621-1625 "Quantitation of human immunodeficiency virus type 1 in the blood of infected persons." [1]) Mr Russell confuses the issue by talking about viral load. This particular paper was in fact measuring the number of infected cells in the periphery. 3,500 per ml. This corresponded to 1 in 400 peripheral mononuclear cells (of which only a subset will be CD4 T cells, around 10% in healthy people as I recall).

He is right in that peripheral viral load over-estimates cell-free infectious virions by around 60,000 fold (I've admitted as much here previously) but as Panteleo et al clearly state in their 1993 Nature paper:

"The peripheral blood does not accurately reflect the actual state of HIV disease, particularly early in the clinical course of HIV infection." [2]

They show 10-100 fold higher levels of virus in the lymph nodes, a concept I have been trying hard for some time to put across. To argue that there isn't enough HIV in the blood stream to cause AIDS is a bit like arguing there isn't enough influenza in tears to cause the flu. Viral load is a surrogate marker of viral replication, NOT the entire viral infection.

His comments regarding the use of uninfected controls are quite right, which is why the data of Hellerstein [3] and Morhi [4] is important. They measure peripheral T cell replication and death rates in treated and untreated HIV+ people, and uninfected controls. They support the initial conclusions of Ho and others, despite the fact that Ho didn't perform as complete an analysis.


Healthy non-HIV infected: CD4 T cell halflife of 87 days.

HIV+ untreated: CD4 T cell halflife of 24 days. T cell replacement rates UNCHANGED despite increased loss.

HIV+ treated: CD4 T cell halflife initially dropped further, then recovered to normal over time (published in a later paper). Replacement rates increased.

Mohri: Normal T cell replication: 0.004 per cell per day

HIV+ T cell replication 0.025 (over 6-fold higher)

Treated HIV+ 0.010 (steady decline over several months after treatment initiation)

Cell death rates were also affected: 0.044 per cell per day in uninfecteds versus 0.129 in untreated HIV patients.

Of interest are the other cell types. CD8 T cells also demonstrated (as previously known through other methods) high levels of replication (0.003 versus 0.023) but unlike CD4 T cells cell death rates were only slightly increased (0.043 versus 0.050). Monocyte kinetics were entirely unaffected by HIV infection. These findings, to me, rather neatly rule out the non-specific causes of AIDS proposed by Duesberg and others.

Critics like Craddock, Duesberg and Bialy (and I would add, Russell!) would prefer us to reject any less-than-perfect analysis (a fact I find ironic considering that in Duesberg's 2003 paper he tries to argue using HIV prevalence figures misrepresented as incidence [5], among other errors). In truth, what one should do is take such results in the setting of other findings and then come to a conclusion. Certainly one should await clarifying work before deciding to reject (or accept of course) any unclear results: but absence of evidence is not evidence of absence.

Regarding PCR, Mr Russell seems unable to comprehend the sheer smallness of viruses. The titres of even an extremely high viral load test are still 10,000 times lower than what Gelderblom estimates would be necessary to perform EM from plasma samples. What method other than PCR would Mr Russell like to see used? In my mind there is no philosophical difference between "amplifying" virions per visual field by centrifugation and amplifying virion genomes per test tube by PCR. There are several non -PCR quantification methods (he mentions the branched chain DNA assay), but I wonder if it's just the amplification step per se he objects to. A virus, ANY virus, requires amplification steps in order to detect it. Such steps include centrifugation, enzyme-linked antibody assays, PCR- based assays. Microscopy itself is an amplification step! Powerful EM's can even visualise the diploid RNA genome of HIV, never mind the virion, but that doesn't mean we should spend weeks scouring microscope slides for such things when we can PCR them up and detect them in a morning's work.

I note that Mr Russell ignores my points regarding DNA virus replication in the nucleus (despite the fact that this puts a hole in his world view on virus replication) and he then goes on to state that all retroviruses are endogenous! Having spent some time studying genetics as well as virology I can attest to the fact that the endogenous phenomenon are well understood and quite distinct from the exogenous viruses. I also find it rather amusing that in one fell swoop Mr Russell has obliterated all of Duesberg's work and that of De Harven, since presumably the viruses they isolated and characterised didn't exist either.

Retroviruses likely evolved from the endogenous entities, that much is suggested from phylogenetic analysis, but Mr Russell's esoteric "epiphenomenon" explanation as to why these sequences magically appear in certain cells that just happen to carry a membrane receptor that this viral agent uses to enter the cell, but in no other cell types, makes no sense. Those are the findings for an exogenous virus. Such sequences should be present in all cell types at all times. The HERV-W virus responsible for Syncytin for example is present in all cells, even though it is only expressed in the placenta. THIS is an endogenous epiphenomenon. HIV is not.

I also note the following quotes, both from Mr Russell.

"No photograph of an isolated 'HIV' particle has ever been published."

But in response to my statement that HIV has been isolated from cultures he says "Precisely."

In addition, HIV has certainly been grown outside of co-cultures, separately from virally-transformed cells, AND in the presence of viral inhibitors [6]. This after all is how the antivirals are developed!! I have never claimed that HIV has been isolated from peripheral blood or semen (so Mr Russell is badly misrepresenting me there), whereas he HAS just claimed that HIV is "never" grown in pure culture. Similarly to the way he claimed that retroviruses were never passed on sexually and that even so such an STD would be spread equally between the sexes. He was wrong on both counts. [7]

If Mr Russell's world view of virology and genetics were supported by the evidence he would have a point to make.

Nick Bennett

1. Ho et al NEJM 1989 321:pp 1621-1625 "Quantitation of human immunodeficiency virus type 1 in the blood of infected persons"

2. Pantaleo et al Nature. 1993 Mar 25;362(6418):355-8. "HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease."

3. Hellerstein, M. et al Nature Medicine (01/99) Vol. 5, No. 1, P. 83; "Directly Measured Kinetics of Circulating T Lymphocytes in Normal and HIV -1-Infected Humans"

4. Mohri et al J Exp Med. 2001 Nov 5;194(9):1277-87. "Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy."

5. Duesberg et al J Biosci. 2003 Jun;28(4):383-412. "The chemical bases of the various AIDS epidemics: recreational drugs, anti-viral chemotherapy and malnutrition.

6. Smith et al J Virol. 1987 Dec;61(12):3769-73. "Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine."

7. Portis et al. J Virol. 1987 Apr;61(4):1037-44. "Horizontal transmission of murine retroviruses."

Competing interests: None declared