May viral (antigen) load be the real crucial tool leading to anergy in a "micro-evolutionary" model of host/virus interaction?

HYPOTHESIS: The hypothesis in the present work is that in host/virus/tumor (antigens) interactions, leading to anergy of the immune system, the Viral (antigen) load plays a crucial and central role, which all interactions turn around. BACKGROUND: Notwithstanding apparent strong favorable evidences, the still prevailing concept of "active virus strategies to escape" may be misleading, since it might hide the cited pivotal role in a wide number of researches. This concept could be easily substituted by a microevolutionary model explaining many unresolved questions and allowing to emerge the role of antigen load conditioned reactions of the host's immune system as motivated choices. EVIDENCES: An anergy induced condition can be detected not only in HCV, but also in the course of persistent viral (e.g. HBV, HIV) and non viral parasitic infections (e.g. Leishmania and Helminths) which share the same host's reactions leading to anergy, independently on the infecting agents. The starting point of those reactions is always time elapsing from the primary infection after a short early (often undetected) period of high viral(antigen) load in the lack of clearance. This latter seems then the only conceivable link between such so different infections determining, as far as HBV and HCV are concerned, also Hepatocarcinoma under indirect facilitating conditions. In a wide majority of studies it seems clearly evident that viral load exerts a main role which contributes to determine host chosen reactions aimed at avoiding dangerous outcomes while controlling viral load. Strong clinical (i.e. both HIV infected patients treated with HAART, and helminths infected people with deworming drugs acting directly on viral and parasitic loads) and experimental studies (i.e. chimpanzees (the only animal model of HCV infection) infected with HBV inocula of different size) are here reported or cited to highlight the crucial role of antigen load also on HIV infection transmission, seroconversion, disease progression, treatment initiation and efficacy. CONCLUDING SUGGESTIONS: The new era for antiviral drugs like protease and polymerase inhibitors that seem to be more efficacious and less toxic than Ribavirin, may open the possibility to verify, when administered during the early phase of HCV infection (eventually helped by an immune-stimulant cytokine as IL-2), whether a precocious significant reduction of viral load (threshold) may allow the host to sustain his strong reactions and clear the virus within the due time, confirming the hypothesis about the crucial role of this tool which may be extended to all the cited infections.

Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity), to prolong its own survival (balance with the virus), to avoid the risk of producing uncontrolled cells (dangerous outcomes). Finally, the postulated negative implications for therapeutic vaccines in cervical cancer, as they really seem to not work till now might be ascribed just to the cited host immune-specific state itself, through an activation induced cell death, elicited by recall antigens (E6/E7 in the case of my wife). Also this latter hypothesis, as well as the previous ones may be of some value to better account for clinical behaviors and researches.